Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Technology Insight: measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer

Nature Clinical Practice Endocrinology & Metabolism volume 4, pages 223–233 (2008)Cite this article

Abstract

Measurement of serum thyroglobulin is primarily used as a tumor marker in the postoperative management of patients with differentiated thyroid cancer. Unfortunately, the technical quality of current thyroglobulin assay methods varies and influences the clinical utility of this test. Two different methodologic approaches are used to measure serum thyroglobulin: the original competitive radioimmunoassay methodology and noncompetitive immunometric assay methods. Although the newer immunometric assays offer the technical benefits of eliminating the use of isotopes, using smaller specimen volumes, and having higher sensitivity potential, shorter turnaround times and the convenience of automation, immunometric assays also have a higher propensity for interference from both thyroglobulin autoantibodies and heterophilic antibodies, if present in the specimen. It is critical that physicians understand the technical limitations inherent in thyroglobulin measurement in order to effectively use this test for the postoperative management of patients with differentiated thyroid cancers.

Key Points

  • Serum thyroglobulin concentrations must be interpreted relative to the mass of thyroid tissue present, any injury effects, the degree of TSH-receptor stimulation and the thyroglobulin assay used

  • Between-assay variability necessitates the use of the same thyroglobulin and thyroglobulin antibody assays for the serial monitoring of patients

  • Because there is a strong relationship between basal thyroglobulin and recombinant human TSH (rhTSH)-stimulated thyroglobulin measurements, sensitive thyroglobulin assays (functional sensitivities ≤0.1 µg/l), when used in conjunction with ultrasound, can greatly reduce the need for rhTSH-stimulated thyroglobulin measurements

  • Immunometric thyroglobulin methods are more prone to interference from thyroglobulin autoantibodies and/or heterophilic antibodies than are radioimmunoassay methods

  • Serial thyroglobulin antibody concentrations can be used as a surrogate tumor marker test

  • Interfering thyroglobulin antibodies may not always be detected using current methods; recovery tests are an unreliable means to detect interference

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Serum thyroglobulin concentrations measured by six currently used methods.
Figure 2: The relationship between basal thyroglobulin and rhTSH-stimulated thyroglobulin in the absence of thyroglobulin autoantibodies.
Figure 3: Relationships between serum thyroglobulin values measured by both an RIA and an IMA as related to detection of TgAb by two different methods.

Similar content being viewed by others

References

  1. Spencer CA (2005) Thyroglobulin. In Werner and Ingbar's “The Thyroid” A Fundamental and Clinical Text, edn 9, 343–359 (Eds Braverman LE and Utiger RD) Philadelphia: Lippincott, Williams and Williams

    Google Scholar 

  2. Schulz R et al. (1989) Evidence for immunological differences between circulating and tissue-derived thyroglobulin in men. Eur J Clin Invest 19: 459–463

    Article  CAS  Google Scholar 

  3. Spencer CA et al. (2005) Clinical impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J Clin Endocrinol Metab 90: 5566–5575

    Article  CAS  Google Scholar 

  4. Cooper DS et al. (2006) Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. The American Thyroid Association Guidelines Taskforce. Thyroid 16: 109–142

    Article  Google Scholar 

  5. Boi F et al. (2006) The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-Tg antibodies. J Clin Endocrinol Metab 91: 1364–1369

    Article  CAS  Google Scholar 

  6. Cunha N et al. (2007) Thyroglobulin detection in fine-needle aspirates of cervical lymph nodes: a technique for the diagnosis of metastatic differentiated thyroid cancer. Eur J Endocrinol 157: 101–107

    Article  CAS  Google Scholar 

  7. Feldt-Rasmussen U et al. (1996) Human thyroglobulin reference material (CRM 457) 2nd part: physicochemical characterization and certification. Ann Biol Clin (Paris) 54: 343–348

    CAS  Google Scholar 

  8. Spencer CA et al. (1996) Current status and performance goals for serum thyroglobulin assays. Clin Chem 42: 164–173

    CAS  PubMed  Google Scholar 

  9. Feldt-Rasmussen U et al. (1980) Long-term variability in serum thyroglobulin and thyroid related hormones in healthy subjects. Acta Endocrinol (Copenh) 95: 328–334

    Article  CAS  Google Scholar 

  10. Arvan P et al. (1997) Intracellular protein transport to the thyrocyte plasma membrane: potential implications for thyroid physiology. Thyroid 7: 89–105

    Article  CAS  Google Scholar 

  11. Di Jeso B et al. (2003) Folding of thyroglobulin in the calnexin/calreticulin pathway and its alteration by loss of Ca2+ from the endoplasmic reticulum. Biochem J 370: 449–458

    Article  CAS  Google Scholar 

  12. McLachlan SM and Rapoport B (2004) Why measure thyroglobulin autoantibodies rather than thyroid peroxidase autoantibodies. Thyroid 14: 510–520

    Article  CAS  Google Scholar 

  13. Prentice L et al. (1995) Monoclonal thyroglobulin autoantibodies: variable region analysis and epitope recognition. J Clin Endocrinol Metab 80: 977–986

    CAS  PubMed  Google Scholar 

  14. Haugen BR et al. (1999) A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 84: 3877–3885

    CAS  PubMed  Google Scholar 

  15. Spencer C et al. (2005) Basal Tg is predictive of rhTSH-stimulated Tg—when patients with differentiated thyroid cancers (DTC) are evaluated by sensitive thyroglobulin (Tg) assays, recombinant human TSH stimulation becomes unnecessary. Thyroid 15 (Suppl 1): O128

    Google Scholar 

  16. Zophel K et al. (2003) Serum thyroglobulin measurements with a high sensitivity enzyme-linked immunosorbent assay: is there a clinical benefit in patients with differentiated thyroid carcinoma. Thyroid 13: 861–865

    Article  Google Scholar 

  17. Baloch Z et al. (2003) Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease. Thyroid 13: 57–67

    Article  Google Scholar 

  18. Davies L and Welch HG (2006) Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA 295: 2164–2167

    Article  CAS  Google Scholar 

  19. Pacini F et al. (2006) European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. Eur J Endocrinol 154: 787–803

    Article  CAS  Google Scholar 

  20. Iervasi A et al. (2007) Clinical relevance of highly sensitive Tg assay in monitoring patients treated for differentiated thyroid cancer. Clin Endocrinol (Oxf) 67: 434–441

    Article  CAS  Google Scholar 

  21. Morgenthaler NG et al. (2002) Technical evaluation of a new immunoradiometric and a new immunoluminometric assay for thyroglobulin. Clin Chem 48: 1077–1083

    CAS  PubMed  Google Scholar 

  22. Schlumberger M et al. (2007) Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients. J Clin Endocrinol Metab 92: 2487–2495

    Article  CAS  Google Scholar 

  23. Mazzaferri EL (2007) Will highly sensitive thyroglobulin assays change the management of thyroid cancer. Clin Endocrinol (Oxf) 67: 321–323

    Article  CAS  Google Scholar 

  24. Pacini F et al. (2003) Recombinant human thyrotropin-stimulated serum thyroglobulin combined with neck ultrasonography has the highest sensitivity in monitoring differentiated thyroid carcinoma. J Clin Endocrinol Metab 88: 3668–3673

    Article  CAS  Google Scholar 

  25. Spencer CA et al. (1993) TRH stimulation test responses employing third and fourth generation TSH assays. J Clin Endocrinol Metab 76: 494–498

    CAS  PubMed  Google Scholar 

  26. Mazzaferri EL et al. (2003) A consensus report of the role of serum thyroglobulin as a monitoring method for low-risk patients with papillary thyroid carcinoma. J Clin Endocrinol Metab 88: 1433–1441

    Article  CAS  Google Scholar 

  27. Smallridge RC et al. (2007) Monitoring thyroglobulin in a sensitive immunoassay has comparable sensitivity to recombinant human TSH-stimulated thyroglobulin in follow-up of thyroid cancer patients. J Clin Endocrinol Metab 92: 82–87

    Article  CAS  Google Scholar 

  28. Pena S et al. (2006) 123I thyroid uptake and thyroid size at 24, 48, and 72 hours after the administration of recombinant human thyroid-stimulating hormone to normal volunteers. J Clin Endocrinol Metab 91: 506–510

    Article  CAS  Google Scholar 

  29. Sawka AM et al. (2004) Clinical review 170: a systematic review and metaanalysis of the effectiveness of radioactive iodine remnant ablation for well-differentiated thyroid cancer. J Clin Endocrinol Metab 89: 3668–3676

    Article  CAS  Google Scholar 

  30. Hay ID (2006) Selective use of radioactive iodine in the postoperative management of patients with papillary and follicular thyroid carcinoma. J Surg Oncol 94: 692–700

    Article  Google Scholar 

  31. McDougall IR and Hay ID (2007) ATA Guidelines: do patients with stage I thyroid cancer benefit from (131)I. Thyroid 17: 595–596

    Article  Google Scholar 

  32. Jonklaas J et al. (2006) Outcomes of patients with differentiated thyroid carcinoma following initial therapy. Thyroid 16: 1229–1242

    Article  Google Scholar 

  33. Eustatia-Rutten CF et al. (2004) Diagnostic value of serum thyroglobulin measurements in the follow-up of differentiated thyroid carcinoma, a structured meta-analysis. Clin Endocrinol (Oxf) 61: 61–74

    Article  CAS  Google Scholar 

  34. Baudin E et al. (2003) Positive predictive value of serum thyroglobulin levels, measured during the first year of follow-up after thyroid hormone withdrawal, in thyroid cancer patients. J Clin Endocrinol Metab 88: 1107–1111

    Article  CAS  Google Scholar 

  35. Kloos RT and Mazzaferri EL (2005) A single recombinant human thyrotropin-stimulated serum thyroglobulin measurement predicts differentiated thyroid carcinoma metastases three to five years later. J Clin Endocrinol Metab 90: 5047–5057

    Article  CAS  Google Scholar 

  36. Levinson SS (1992) The nature of heterophilic antibodies and their role in immunoassay interference. J Clin Immunoassay 15: 108–115

    Google Scholar 

  37. Preissner CM et al. (2003) Phantoms in the assay tube: heterophile antibody interferences in serum thyroglobulin assays. J Clin Endocrinol Metab 88: 3069–3074

    Article  CAS  Google Scholar 

  38. Giovanella L and Ghelfo A (2007) Undetectable serum thyroglobulin due to negative interference of heterophile antibodies in relapsing thyroid carcinoma. Clin Chem 53: 1871–1872

    Article  CAS  Google Scholar 

  39. Kazmierczak SC et al. (2000) Transient nature of interference effects from heterophile antibodies: examples of interference with cardiac marker measurements. Clin Chem Lab Med 38: 33–39

    Article  CAS  Google Scholar 

  40. Choi WW et al. (2005) Aberrant thyroid testing results in a clinically euthyroid patient who had received a tumor vaccine. Clin Chem 51: 673–675

    Article  CAS  Google Scholar 

  41. Spencer CA et al. (1998) Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 83: 1121–1127

    CAS  PubMed  Google Scholar 

  42. Gorges R et al. (2005) Development and clinical impact of thyroglobulin antibodies in patients with differentiated thyroid carcinoma during the first 3 years after thyroidectomy. Eur J Endocrinol 153: 49–55

    Article  CAS  Google Scholar 

  43. Hollowell JG et al. (2002) Serum thyrotropin, thyroxine, and thyroid antibodies in the United States population (1988 to 1994): NHANES III. J Clin Endocrinol Metab 87: 489–499

    Article  CAS  Google Scholar 

  44. Kastrup J et al. (1985) An enzyme linked immunosorbent assay (ELISA) for measurement of human serum thyroglobulin. Evaluation of the influence of thyroglobulin auto-antibodies. Scand J Clin Lab Invest 45: 471–476

    Article  CAS  Google Scholar 

  45. Spencer CA et al. (1999) Detection of residual and recurrent differentiated thyroid carcinoma by serum thyroglobulin measurement. Thyroid 9: 435–441

    Article  CAS  Google Scholar 

  46. Mariotti S et al. (1995) Assay of thyroglobulin in serum with thyroglobulin autoantibodies: an unobtainable goal. J Clin Endocrinol Metab 80: 468–472

    Article  CAS  Google Scholar 

  47. Uller RP and Van Herle AJ (1978) Effect of therapy on serum thyroglobulin levels in patients with Graves' disease. J Clin Endocrinol Metab 46: 747–755

    Article  CAS  Google Scholar 

  48. Henry M et al. (1990) Epitope mapping of human thyroglobulin: heterogeneous recognition by thyroid pathologic sera. J Immunol 145: 3692–3698

    CAS  PubMed  Google Scholar 

  49. Okosieme OE et al. (2005) Thyroglobulin antibodies in serum of patients with differentiated thyroid cancer: relationship between epitope specificities and thyroglobulin recovery. Clin Chem 51: 729–734

    Article  CAS  Google Scholar 

  50. Estienne B et al. (1998) Comparative mapping of cloned human and murine antithyroglobulin antibodies: recognition by human antibodies of an immunodominant region. Thyroid 8: 643–646

    Article  CAS  Google Scholar 

  51. Erali M et al. (1996) ELISA for thyroglobulin in serum: recovery studies to evaluate autoantibody interference and reliability of thyroglobulin values. Clin Chem 42: 766–770

    CAS  PubMed  Google Scholar 

  52. Marquet PY et al. (1996) Highly sensitive immunoradiometric assay for serum thyroglobulin with minimal interference from autoantibodies. Clin Chem 42: 258–262

    CAS  PubMed  Google Scholar 

  53. Schneider AB and Pervos R (1978) Radioimmunoassay of human thyroglobulin: effect of antithyroglobulin autoantibodies. J. Clin Endocrinol Metab 47: 126–137

    Article  CAS  Google Scholar 

  54. Feldt-Rasmussen U and Rasmussen AK (1985) Serum thyroglobulin (Tg) in presence of thyroglobulin autoantibodies (TgAb). Clinical and methodological relevance of the interaction between Tg and TgAb in vitro and in vivo. J Endocrinol Invest 8: 571–576

    Article  CAS  Google Scholar 

  55. Feldt-Rasmussen U et al. (1980) Sequential changes in serum thyroglobulin (Tg) and its autoantibodies (TgAb) following subtotal thyroidectomy of patients with preoperatively detectable TgAb. Clin Endocrinol (Oxf) 12: 29–38

    Article  CAS  Google Scholar 

  56. Feldt-Rasmussen U and Schlumberger M (1988) European interlaboratory comparison of serum thyroglobulin measurement. J Endocrinol Invest 11: 175–181

    Article  CAS  Google Scholar 

  57. Kato R et al. (2000) A new assay for thyroglobulin concentration in serum using monoclonal antibodies against synthetic peptides. Clin Chim Acta 298: 69–84

    Article  CAS  Google Scholar 

  58. Massart C and Maugendre D (2002) Importance of the detection method for thyroglobulin antibodies for the validity of thyroglobulin measurements in sera from patients with Graves disease. Clin Chem 48: 102–107

    CAS  PubMed  Google Scholar 

  59. Benvenga S et al. (2002) Heterogeneity of the thyroglobulin epitopes associated with circulating thyroid hormone autoantibodies in Hashimoto's thyroiditis and non-autoimmune thyroid diseases. J Endocrinol Invest 25: 977–982

    Article  CAS  Google Scholar 

  60. Chung JK et al. (2002) Clinical significance of elevated level of serum antithyroglobulin antibody in patients with differentiated thyroid cancer after thyroid ablation. Clin Endocrinol (Oxf) 57: 215–221

    Article  Google Scholar 

  61. Tumino S and Belfiore A (2000) Appearance of antithyroglobulin antibodies as the sole sign of metastatic lymph nodes in a patient operated on for papillary thyroid cancer: a case report. Thyroid 10: 431–433

    Article  CAS  Google Scholar 

  62. Spencer C and Fatemi S (2005) Thyroglobulin measurements in thyroid cancer evaluation and surveillance. In Pathogenesis and Treatment of Thyroid Neoplasms. Advances in Molecular and Cellular Endocrinology, vol 4, 83–105 (Ed. Haugen B) Amsterdam: Elsevier Sciences

    Google Scholar 

  63. Weigle WO and High GJ (1967) The behavior of autologous thyroglobulin in the circulation of rabbits immunized with either heterologous or altered homologous thyroglobulin. J Immunol 98: 1105–1114

    CAS  PubMed  Google Scholar 

  64. Chiovato L et al. (2003) Disappearance of humoral thyroid autoimmunity after complete removal of thyroid antigens. Ann Intern Med 139: 346–351

    Article  CAS  Google Scholar 

  65. Thomas D et al. (2007) Possible reasons for different pattern disappearance of thyroglobulin and thyroid peroxidase autoantibodies in patients with differentiated thyroid carcinoma following total thyroidectomy and iodine-131 ablation. J Endocrinol Invest 30: 173–180

    Article  CAS  Google Scholar 

  66. Feldt-Rasmussen U et al. (1982) Thyroid stimulating antibodies, thyroglobulin antibodies and serum proteins during treatment of Graves' disease with radioiodine or propylthiouracil. Allergy 37: 161–167

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. CA Spencer is Professor of Medicine and JS LoPresti is Associate Professor of Medicine, University of Southern California, Los Angeles, CA, USA.,

    Carole A Spencer & Jonathan S LoPresti

Authors
  1. Carole A Spencer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jonathan S LoPresti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Carole A Spencer.

Ethics declarations

Competing interests

CA Spencer is a Consultant for Abbott. JS LoPresti declared no competing interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Spencer, C., LoPresti, J. Technology Insight: measuring thyroglobulin and thyroglobulin autoantibody in patients with differentiated thyroid cancer. Nat Rev Endocrinol 4, 223–233 (2008). https://doi.org/10.1038/ncpendmet0757

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpendmet0757

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing