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Test ID: HTGR Thyroglobulin, Tumor Marker Reflex, Serum

Reporting Name

Thyroglobulin Reflex to MS or IA

Useful For

Reporting of accurate thyroglobulin results, depending on the antithyroglobulin antibodies status of the patient

 

Accurate measurement of serum thyroglobulin in patients with known or suspected antithyroglobulin autoantibodies or possible heterophile antibodies

Clinical Information

Thyroglobulin (Tg) is a thyroid-specific glycoprotein (approximately 660 KDa) that serves as the source for thyroxine (T4) and triiodothyronine (T3) production within the lumen of thyroid follicles. For T4 and T3 release, Tg is reabsorbed into thyrocytes and proteolytically degraded, liberating T4 and T3 for secretion. Small amounts of intact Tg are secreted alongside T4 and T3 and are detectable in the serum of healthy individuals, with levels roughly paralleling thyroid size (0.5-1.0 ng/mL Tg per gram thyroid tissue, depending on thyroid-stimulating hormone [TSH] level). In situations of disordered thyroid growth (eg, goiter), increased thyroid activity (eg, Graves disease), or glandular destruction (eg, thyroiditis) larger amounts of Tg may be released into the circulation.

 

Clinically, the main use of serum Tg measurements is in the follow-up of differentiated follicular cell-derived thyroid carcinoma. Because Tg is thyroid-specific, serum Tg concentrations should be undetectable, or very low, after the thyroid gland is removed during treatment for thyroid cancer.

 

Current clinical guidelines consider a serum Tg of more than1 ng/mL in an athyrotic individual as suspicious of possible residual or recurrent disease. To improve diagnostic accuracy, it is recommended that at least initially this measurement is obtained after TSH stimulation, either following thyroid hormone withdrawal, or after injection of recombinant human TSH. Most patients will have a relatively low risk of recurrence, and will thereafter only require unstimulated Tg measurement. If unstimulated (on thyroxine) serum Tg measurements are less than 0.1 to 0.2 ng/mL, the risk of disease is below 1%. Patients with higher Tg levels, who have no demonstrable remnant of thyroid tissue, might require additional testing, such as further stimulated Tg measurements, neck ultrasound, or isotope imaging. A stimulated Tg above 2 ng/mL is considered suspicious.

 

The presence of anti-thyroglobulin autoantibodies (TgAb), which occur in 15% to 30% of thyroid cancer patients, could lead to misleading Tg results. In immunometric assays, the presence of TgAb can lead to false low measurement; whereas it might lead to false high results in competitive assays. Traditionally, there have been no reliable means to obtain accurate Tg measurements in patients with TgAb. However, recently, trypsin digestion of serum proteins, which cuts both antibodies and Tg into predictable fragments, has allowed accurate quantification of Tg in samples with antibody interferences through measurement of Tg-specific tryptic peptides by mass spectrometry.

Interpretation

Current guidelines recommend measurement of thyroglobulin (Tg) with a sensitive immunoassay - limit of quantification less than 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 anti-thyroglobulin autoantibodies (TgAb) should also be measured, preferably with a method that allows detection of low concentrations of TgAb. 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 less than 1.0 ng/mL, the sample should be remeasured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This will allow confident detection of Tg in the presence of TgAb down to 0.5 ng/mL (risk of residual/recurrent disease <1%-3%).

 

Samples from patients with Tg concentrations greater than 1.0 ng/mL might not require Tg measurement by mass spectrometry, because current guidelines suggest further work-up might be necessary above this threshold. However the positive predictive value for residual/recurrent disease is modest when Tg is just above this threshold (3%-25%) in athyrotic patients. Above 10 ng/mL, the risk of residual/recurrent disease is at least 25%, with many studies showing 60% to greater than 90% risks. In selected patients, it might therefore also be useful to test TgAb positive samples by mass spectrometry, even if the Tg concentration is greater than 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 of 1.0 to 10 ng/mL, owing to remnant Tg secretion, regardless of the presence or absence of residual/recurrent cancer.

 

It has been determined that the presence of anti-thyroglobulin autoantibodies (TgAb) in serum can lead to underestimation of Tg concentration by immunometric methods. When TgAb are present in samples with detectable Tg, the Tg values may be underestimated by up to 60% in immunoassays. In addition, some specimens containing TgAb which are negative for Tg by immunoassay tested positive by LC-MS/MS. Therefore, measuring of Tg by LC-MS/MS is the preferred method in TgAb positive patients. The listed decision levels are for thyroid cancer follow-up of athyrotic patients and apply to unstimulated and stimulated thyroglobulin measurements. Decision levels are based on best practice guidelines and the literature, which includes Mayo Clinic studies.

 

Decision levels for thyroid cancer patients, who are not completely athyrotic (ie, patient has some remnant normal thyroid tissue), have not been established, but are likely to be somewhat higher: remnant normal thyroid tissue contributes to serum Tg concentrations 0.2 to 1.0 ng/mL per gram of remnant tissue, depending on the TSH level.

 

Thyroglobulin by Mass Spectrometry:

Tg <0.2 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements, and radioiodine ablation status. Undetectable Tg levels in athyrotic individuals on suppression therapy indicate a minimal risk (<1%-2%) of clinically detectable recurrent papillary/follicular thyroid cancer.

 

Tg ≥0.2 ng/mL to 2.0 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements, and radioiodine ablation status. Tg levels of 0.2-2.0 ng/mL in athyrotic individuals on suppressive therapy indicate a low risk of clinically detectable recurrent papillary/follicular thyroid cancer.

 

Tg 2.1 ng/mL to 9.9 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements and radioiodine ablation status. Tg levels of 2.1-9.9 ng/mL in athyrotic individuals on suppression therapy indicate an increased risk of clinically detectable recurrent papillary/follicular thyroid cancer.

 

Tg ≥10 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements and radioiodine ablation status. Tg levels of ≥10 ng/mL in athyrotic individuals on suppressive therapy indicate a significant (>25%) risk of clinically detectable recurrent papillary/follicular thyroid cancer.

 

Thyroglobulin by Immunoassay:

Tg <0.1 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements and radioiodine ablation status. Tg levels <0.1 ng/mL in athyrotic individuals on suppressive therapy indicate a minimal risk (<1%-2%) of clinically detectable recurrent papillary/follicular thyroid cancer.

 

Tg ≥0.1 to 2.0 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements and radioiodine ablation status. Tg levels 0.1 to 2.0 ng/mL in athyrotic individuals on suppressive therapy indicate a low risk of clinically detectable recurrent papillary/follicular thyroid cancer.

 

Tg 2.1 ng/mL to 9.9 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements and radioiodine ablation status. Tg levels 2.1 to 9.9 ng/mL in athyrotic individuals on suppressive therapy indicate an increased risk of clinically detectable recurrent papillary/follicular thyroid cancer.

 

Tg ≥10 ng/mL: Tg levels must be interpreted in the context of TSH levels, serial Tg measurements and radioiodine ablation status. Tg levels ≥10 ng/mL in athyrotic individuals on suppressive therapy indicate a significant risk (>25%) of clinically detectable recurrent papillary/follicular thyroid cancer.

Testing Algorithm

This test begins with the analysis of thyroglobulin antibody by immunoassay. If the thyroglobulin antibody result is negative (<1.8 IU/mL), then thyroglobulin testing will be performed by immunoassay.

 

If the thyroglobulin antibody result is positive (≥1.8 IU/mL), then thyroglobulin testing will be performed by mass spectrometry.

Reflex Tests

Test ID Reporting Name Available Separately Always Performed
HTGT Thyroglobulin, Tumor Marker, IA, S No No
TGMS Thyroglobulin, Mass Spec., S Yes No

Analytic Time

1 day if thyroglobulin antibody result is negative or 2 to 3 days if positive

Day(s) and Time(s) Performed

TGABR and HTGT:

Monday through Friday; 6 a.m.-12 a.m.

Saturday; 6 a.m.-6 p.m.

 

TGMS:

Monday through Friday; 4 p.m.

Clinical Reference

1. Grebe SKG: Diagnosis and management of thyroid carcinoma: A focus on serum thyroglobulin. Expert Rev Endocrinol Metab. 2009;4:25-43

2. Cooper DS, Doherty GM, Haugen BR, et al: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19:1167-1214

3. Pacini F, Catagana MG, Brilli L, Pentheroudakis G, on behalf of the ESMO Guidelines Working Group: Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21 Suppl 5:v214-v219

4. National Comprehensive Cancer Network (NCCN) guidelines for treatment of cancer by site: version 2.2013: Thyroid Carcinoma. Accessed August 25, 2020. Available at: https://www.uptodate.com/contents/differentiated-thyroid-cancer-role-of-serum-thyroglobulin

Method Name

Immunoenzymatic Assay

Specimen Type

Serum Red


Specimen Required


Patient Preparation: For 12 hours before specimen collection do not take multivitamins or dietary supplements containing biotin (vitamin B7), which is commonly found in hair, skin, and nail supplements and multivitamins.

Collection Container/Tube: Red top

Submission Container/Tube: Plastic vial

Specimen Volume: 1 mL


Specimen Minimum Volume

See Specimen Required

Specimen Stability Information

Specimen Type Temperature Time Special Container
Serum Red Refrigerated (preferred) 7 days
  Frozen  30 days

Reference Values

Thyroglobulin Antibody: <1.8 IU/mL

Test Classification

This test has been cleared, approved or is exempt by the U.S. Food and Drug Administration and is used per manufacturer's instructions. Performance characteristics were verified by Mayo Clinic in a manner consistent with CLIA requirements.

CPT Code Information

86800

LOINC Code Information

Test ID Test Order Name Order LOINC Value
HTGR Thyroglobulin Reflex to MS or IA 56536-6

 

Result ID Test Result Name Result LOINC Value
TGABR Thyroglobulin Antibody, S 56536-6
Mayo Clinic Laboratories | Endocrinology Catalog Additional Information:

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