DIAGNOSIS OF ENDOCRINE DISEASE: Thyroglobulin measurement using highly sensitive assays in patients with differentiated thyroid cancer: a clinical position paper

Differentiated thyroid cancer (DTC) is the most common endocrine cancer and its incidence has increased in recent decades. Initial treatment usually consists of total thyroidectomy followed by ablation of thyroid remnants by iodine-131. As thyroid cells are assumed to be the only source of thyroglobulin (Tg) in the human body, circulating Tg serves as a biochemical marker of persistent or recurrent disease in DTC follow-up. Currently, standard follow-up for DTC comprises Tg measurement and neck ultrasound combined, when indicated, with an additional radioiodine scan. Measurement of Tg after stimulation by endogenous or exogenous TSH is recommended by current clinical guidelines to detect occult disease with a maximum sensitivity due to the suboptimal sensitivity of older Tg assays. However, the development of new highly sensitive Tg assays with improved analytical sensitivity and precision at low concentrations now allows detection of very low Tg concentrations reflecting minimal amounts of thyroid tissue without the need for TSH stimulation. Use of these highly sensitive Tg assays has not yet been incorporated into clinical guidelines but they will, we believe, be used by physicians caring for patients with DTC. The aim of this clinical position paper is, therefore, to offer advice on the various aspects and implications of using these highly sensitive Tg assays in the clinical care of patients with DTC.

[1]  J. Vieira,et al.  Basal Serum Thyroglobulin Measured by a Second-Generation Assay Is Equivalent to Stimulated Thyroglobulin in Identifying Metastases in Patients with Differentiated Thyroid Cancer with Low or Intermediate Risk of Recurrence , 2014, European Thyroid Journal.

[2]  P. Trimboli,et al.  Unstimulated highly sensitive thyroglobulin in follow-up of differentiated thyroid cancer patients: a meta-analysis. , 2014, The Journal of clinical endocrinology and metabolism.

[3]  E. Baudin,et al.  Ultrasensitive serum thyroglobulin measurement is useful for the follow-up of patients treated with total thyroidectomy without radioactive iodine ablation. , 2013, European journal of endocrinology.

[4]  L. Duntas,et al.  Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: a clinical position statement. , 2013, Thyroid : official journal of the American Thyroid Association.

[5]  R. Paschke,et al.  2013 European Thyroid Association Guidelines for Cervical Ultrasound Scan and Ultrasound-Guided Techniques in the Postoperative Management of Patients with Thyroid Cancer , 2013, European Thyroid Journal.

[6]  A. Buck,et al.  Relationship Between Antithyroglobulin Autoantibodies and Thyroglobulin Recovery Rates Using Different Thyroglobulin Concentrations in the Recovery Buffer , 2013, Hormone and Metabolic Research.

[7]  G. Beckett,et al.  Discordance in thyroglobulin measurements by radioimmunoassay and immunometric assay: a useful means of identifying thyroglobulin assay interference , 2013, Annals of clinical biochemistry.

[8]  P. Rosário,et al.  Follow-up of Patients with Low-risk Papillary Thyroid Carcinoma and Undetectable Basal Serum Thyroglobulin After Ablation Measured with a Sensitive Assay: A Prospective Study , 2013, Hormone and Metabolic Research.

[9]  A. Hoofnagle,et al.  Clinical review: improving the measurement of serum thyroglobulin with mass spectrometry. , 2013, The Journal of clinical endocrinology and metabolism.

[10]  R. Kloos,et al.  In thyroidectomized patients with thyroid cancer, a serum thyrotropin of 30 μU/mL after thyroxine withdrawal is not always adequate for detecting an elevated stimulated serum thyroglobulin. , 2013, Thyroid : official journal of the American Thyroid Association.

[11]  L. Ceriani,et al.  Evaluation of the BRAHMS Kryptor® Thyroglobulin Minirecovery Test in patients with differentiated thyroid carcinoma , 2012, Clinical chemistry and laboratory medicine.

[12]  R. Tuttle,et al.  Even without additional therapy, serum thyroglobulin concentrations often decline for years after total thyroidectomy and radioactive remnant ablation in patients with differentiated thyroid cancer. , 2012, Thyroid : official journal of the American Thyroid Association.

[13]  J. Franklyn,et al.  Can we interpret serum thyroglobulin results? , 2012, Annals of clinical biochemistry.

[14]  R. Smallridge,et al.  Undetectable sensitive serum thyroglobulin (<0.1 ng/ml) in 163 patients with follicular cell-derived thyroid cancer: results of rhTSH stimulation and neck ultrasonography and long-term biochemical and clinical follow-up. , 2012, The Journal of clinical endocrinology and metabolism.

[15]  T. Montesano,et al.  Long-term surveillance of papillary thyroid cancer patients who do not undergo postoperative radioiodine remnant ablation: is there a role for serum thyroglobulin measurement? , 2012, The Journal of clinical endocrinology and metabolism.

[16]  M. Bailey,et al.  Incidence and implications of negative serum thyroglobulin but positive I‐131 whole‐body scans in patients with well‐differentiated thyroid cancer prepared with rhTSH or thyroid hormone withdrawal , 2012, Clinical endocrinology.

[17]  A. Buck,et al.  Impact of moderate vs stringent TSH suppression on survival in advanced differentiated thyroid carcinoma , 2012, Clinical endocrinology.

[18]  M. Luster,et al.  Radioiodine for remnant ablation and therapy of metastatic disease , 2011, Nature Reviews Endocrinology.

[19]  B. Lie,et al.  Multiple loci in the HLA complex are associated with Addison's disease. , 2011, The Journal of clinical endocrinology and metabolism.

[20]  A. Algeciras-Schimnich,et al.  The Roche Elecsys and Siemens-Centaur thyroglobulin autoantibody assays show comparable clinical performance to the recently unavailable Beckman-Coulter access thyroglobulin autoantibody assay in identifying samples with potentially false-low thyroglobulin measurements due to thyroglobulin autoantib , 2011, Thyroid : official journal of the American Thyroid Association.

[21]  R. Vigneri,et al.  Risk-adapted management of differentiated thyroid cancer assessed by a sensitive measurement of basal serum thyroglobulin. , 2011, The Journal of clinical endocrinology and metabolism.

[22]  F. Pacini,et al.  The use of ultrasensitive thyroglobulin assays reduces but does not abolish the need for TSH stimulation in patients with differentiated thyroid carcinoma , 2011, Journal of endocrinological investigation.

[23]  C. Spencer,et al.  Current thyroglobulin autoantibody (TgAb) assays often fail to detect interfering TgAb that can result in the reporting of falsely low/undetectable serum Tg IMA values for patients with differentiated thyroid cancer. , 2011, The Journal of clinical endocrinology and metabolism.

[24]  L. Ceriani,et al.  Undetectable Thyroglobulin in Patients With Differentiated Thyroid Carcinoma and Residual Radioiodine Uptake on a Postablation Whole-Body Scan , 2011, Clinical nuclear medicine.

[25]  P. Singer,et al.  Serum Basal thyroglobulin measured by a second-generation assay correlates with the recombinant human thyrotropin-stimulated thyroglobulin response in patients treated for differentiated thyroid cancer. , 2010, Thyroid : official journal of the American Thyroid Association.

[26]  K. Wäschle,et al.  Heterophile Antibodies Rarely Influence the Measurement of Thyroglobulin and Thyroglobulin Antibodies in Differentiated Thyroid Cancer Patients , 2010, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[27]  U. Feldt-Rasmussen,et al.  Autoimmunity in differentiated thyroid cancer: Significance and related clinical problems , 2010, Hormones.

[28]  S. Jefferies,et al.  Concordance between thyroglobulin antibody assays , 2010, Annals of clinical biochemistry.

[29]  M. Luster,et al.  No survival difference after successful 131I ablation between patients with initially low-risk and high-risk differentiated thyroid cancer , 2010, European Journal of Nuclear Medicine and Molecular Imaging.

[30]  Stephanie L. Lee,et al.  Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. , 2009, Thyroid : official journal of the American Thyroid Association.

[31]  L. Ceriani,et al.  Postsurgery serum thyroglobulin disappearance kinetic in patients with differentiated thyroid carcinoma , 2009, Head & neck.

[32]  L. Ceriani,et al.  Heterophile antibodies may falsely increase or decrease thyroglobulin measurement in patients with differentiated thyroid carcinoma , 2009, Clinical chemistry and laboratory medicine.

[33]  P. Clark.  Laboratory services for thyroglobulin and implications for monitoring of differentiated thyroid cancer , 2009, Journal of Clinical Pathology.

[34]  M. Panteghini.  Assay-related issues in the measurement of cardiac troponins. , 2009, Clinica chimica acta; international journal of clinical chemistry.

[35]  L. Giovanella.  False-negative thyroglobulin measurement in recurrent/metastatic thyroid carcinomas , 2009, European Journal of Nuclear Medicine and Molecular Imaging.

[36]  S. Grebe.  Diagnosis and management of thyroid carcinoma: a focus on serum thyroglobulin , 2009 .

[37]  F. Sweep,et al.  Assay bias may invalidate decision limits and affect comparability of serum thyroglobulin assay methods: an approach to reduce interpretation differences. , 2008, Clinica chimica acta; international journal of clinical chemistry.

[38]  D. Armbruster,et al.  Limit of blank, limit of detection and limit of quantitation. , 2008, The Clinical biochemist. Reviews.

[39]  S. Purisch,et al.  Does a highly sensitive thyroglobulin (Tg) assay change the clinical management of low‐risk patients with thyroid cancer with Tg on T4 < 1 ng/ml determined by traditional assays? , 2008, Clinical endocrinology.

[40]  L. Ceriani,et al.  Preoperative undetectable serum thyroglobulin in differentiated thyroid carcinoma: incidence, causes and management strategy , 2007, Clinical endocrinology.

[41]  M. Ferdeghini,et al.  Clinical relevance of highly sensitive Tg assay in monitoring patients treated for differentiated thyroid cancer , 2007, Clinical endocrinology.

[42]  B. Wolffenbuttel,et al.  A Sensitive Tg Assay or rhTSH Stimulated Tg: What's the Best in the Long-Term Follow-Up of Patients with Differentiated Thyroid Carcinoma? , 2007, PloS one.

[43]  S. Koscielny,et al.  Comparison of seven serum thyroglobulin assays in the follow-up of papillary and follicular thyroid cancer patients. , 2007, The Journal of clinical endocrinology and metabolism.

[44]  J. Kievit,et al.  Serum thyroglobulin concentrations predict disease‐free remission and death in differentiated thyroid carcinoma , 2006, Clinical endocrinology.

[45]  B. Wolffenbuttel,et al.  Thyroglobulin (Tg) recovery testing with quantitative Tg antibody measurement for determining interference in serum Tg assays in differentiated thyroid carcinoma. , 2006, Clinical chemistry.

[46]  W. Wiersinga,et al.  European consensus for the management of patients with differentiated thyroid carcinoma of the follicular epithelium. , 2006, European journal of endocrinology.

[47]  M. Schlumberger.  Is stimulation of thyroglobulin (Tg) useful in low‐risk patients with thyroid carcinoma and undetectable Tg on thyroxin and negative neck ultrasound? * , 2005, Clinical endocrinology.

[48]  C. Annicchiarico,et al.  Diagnostic performance of a new highly sensitive thyroglobulin immunoassay. , 2004, The Journal of endocrinology.

[49]  K. Zöphel,et al.  Serum thyroglobulin measurements with a high sensitivity enzyme-linked immunosorbent assay: is there a clinical benefit in patients with differentiated thyroid carcinoma? , 2003, Thyroid : official journal of the American Thyroid Association.

[50]  D. O'Kane,et al.  Phantoms in the assay tube: heterophile antibody interferences in serum thyroglobulin assays. , 2003, The Journal of clinical endocrinology and metabolism.

[51]  L. Demers,et al.  Laboratory medicine practice guidelines: laboratory support for the diagnosis and monitoring of thyroid disease , 2003, Clinical endocrinology.

[52]  F. Pacini.  Follow-up of differentiated thyroid cancer , 2002, European Journal of Nuclear Medicine and Molecular Imaging.

[53]  L. Wartofsky.  Using baseline and recombinant human TSH-stimulated Tg measurements to manage thyroid cancer without diagnostic (131)I scanning. , 2002, The Journal of clinical endocrinology and metabolism.

[54]  N. Bizzaro,et al.  Immunoassay of Anti-Thyroid Autoantibodies: High Analytical Variability in Second Generation Methods , 2002, Clinical chemistry and laboratory medicine.

[55]  L. Ceriani,et al.  High-Sensitivity Human Thyroglobulin (hTG) Immunoradiometric Assay in the Follow-up of Patients with Differentiated Thyroid Cancer , 2002, Clinical chemistry and laboratory medicine.

[56]  A. Pinchera,et al.  Prediction of disease status by recombinant human TSH-stimulated serum Tg in the postsurgical follow-up of differentiated thyroid carcinoma. , 2001, The Journal of clinical endocrinology and metabolism.

[57]  K. Zöphel,et al.  A high-sensitivity enzyme-linked immunosorbent assay for serum thyroglobulin. , 2001, Thyroid : official journal of the American Thyroid Association.

[58]  Z. Baloch,et al.  Laboratory medicine practice guidelines. Laboratory support for the diagnosis and monitoring of thyroid disease. , 2003, Thyroid : official journal of the American Thyroid Association.

[59]  P. Singer,et al.  Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. , 1998, The Journal of clinical endocrinology and metabolism.

[60]  M. Schlumberger,et al.  Papillary and follicular thyroid carcinoma. , 1998, The New England journal of medicine.

[61]  S. K. Verma,et al.  Diagnosis and monitoring of thyroid diseases. , 1996, Indian journal of pathology & microbiology.

[62]  M. Schlumberger,et al.  European interlaboratory comparison of serum thyroglobulin measurement , 1988, Journal of endocrinological investigation.

[63]  K. Johansen,et al.  Thyroid Stimulating Antibodies, Thyroglobulin Antibodies and Serum Proteins during Treatment of Graves’ Disease with Radioiodine or Propylthouracil , 1982, Allergy.

[64]  Shinichiro,et al.  Carcinoma , 1906, The Hospital.

[65]  A. Buck,et al.  Life expectancy is reduced in differentiated thyroid cancer patients ≥ 45 years old with extensive local tumor invasion, lateral lymph node, or distant metastases at diagnosis and normal in all other DTC patients. , 2013, The Journal of clinical endocrinology and metabolism.

[66]  M. Gapany.  No survival difference after successful 131I ablation between patients with initially low-risk and high-risk differentiated thyroid cancer , 2011 .

[67]  L. Giovanella.  Highly sensitive thyroglobulin measurements in differentiated thyroid carcinoma management , 2008, Clinical chemistry and laboratory medicine.

[68]  T. P. Fox,et al.  Monitoring thyroglobulin in a sensitive immunoassay has comparable sensitivity to recombinant human tsh-stimulated thyroglobulin in follow-up of thyroid cancer patients. , 2007, The Journal of clinical endocrinology and metabolism.

[69]  L. Ceriani,et al.  Thyroglobulin assay during thyroxine treatment in low-risk differentiated thyroid cancer management: comparison with recombinant human thyrotropin-stimulated assay and imaging procedures , 2006, Clinical chemistry and laboratory medicine.

[70]  D. M.,et al.  Protocols for Determination of Limits of Detection and Limits of Quantitation; Approved Guidelines , 2004 .

[71]  B. Haugen,et al.  Clinical comparison of whole-body radioiodine scan and serum thyroglobulin after stimulation with recombinant human thyrotropin. , 2002, Thyroid : official journal of the American Thyroid Association.

[72]  M. Schlumberger,et al.  Human thyroglobulin reference material (CRM 457). 1st Part: Assessment of homogeneity, stability and immunoreactivity. , 1996, Annales de biologie clinique.

[73]  C. Spencer,et al.  Current status and performance goals for serum thyroglobulin assays. , 1996, Clinical chemistry.

[74]  M. Schlumberger,et al.  Human thyroglobulin reference material (CRM 457). 2nd Part: Physicochemical characterization and certification. , 1996, Annales de biologie clinique.