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Epic Code LAB864 Thyroglobulin, Tumor Marker, Serum

Additional Codes

Mayo Code: HTG2

Internal Alias:10781

Epic: LAB 864

Cerner: 3069

Reporting Name

Thyroglobulin, Tumor Marker

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 than 1 ng/mL in an athyrotic individual as suspicious of possible residual or recurrent disease. To improve diagnostic accuracy, it is recommended that this measurement be initially 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 antithyroglobulin 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 results; 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 by mass spectrometry. See TGMS / Thyroglobulin Mass Spectrometry, Serum for accurate analysis of patients who are known to be TgAb positive. If TgAb status is unknown, see HTGR / Thyroglobulin, Tumor Marker Reflex to LC-MS/MS or Immunoassay. When HTGR is ordered, TgAb testing is performed first. If TgAb is negative (<1.8 IU/mL), Tg is assayed by immunoassay (sensitive down to 0.1 ng/mL). If TgAb is positive, Tg is assayed by mass spectrometry (sensitive down to 0.2 ng/mL).

Useful For

Follow-up of patients with differentiated thyroid cancers after thyroidectomy and radioactive iodine ablation

Performing Laboratory

Mayo Clinic Laboratories in Rochester


Ordering Guidance


For accurate analysis of patients who are known to be thyroglobulin antibody positive, order TGMS / Thyroglobulin Mass Spectrometry, Serum.



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 (serum gel/SST are not acceptable)

Submission Container/Tube: Plastic vial

Specimen Volume: 1 mL

Collection Instructions: Centrifuge and aliquot serum into a plastic vial.


Laboratory Test Directory Note:

COLLECTION NOTE: Volumes listed are in serum or plasma, draw approximately 2 1/2 times the requested volume in whole blood.

Specimen Type

Serum Red

Specimen Minimum Volume

0.5 mL

Specimen Stability Information

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

Day(s) Performed

Monday through Friday

Reject Due To

Gross hemolysis Reject
Gross lipemia OK

Reference Values

THYROGLOBULIN, TUMOR MARKER

Athyrotic: <0.1 ng/mL

Intact thyroid ≤33 ng/mL

 

THYROGLOBULIN ANTIBODY

<1.8 IU/mL

Reference values apply to all ages.

Interpretation

Current guidelines recommend measurement of thyroglobulin (Tg) with a sensitive immunoassay (limit of quantification <1.0 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 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 using an immunometric assay. If the apparent Tg concentration is <1.0 ng/mL, the sample should be remeasured by mass spectrometry. This will allow accurate detection of Tg, in the presence of TgAb, down to 0.2 ng/mL (risk of residual/recurrent disease <1%-3%).

 

Samples from patients with Tg concentrations >1.0 ng/mL might not require Tg measurement by mass spectrometry because current guidelines suggest further workup 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 >90% risks. In selected patients, therefore, it might also be useful to test TgAb positive samples by mass spectrometry, even if the Tg concentration is >1.0 ng/mL, but not above 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 antithyroglobulin 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, approximately 20% of specimens containing TgAb, which are negative for Tg by immunoassay, tested positive by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Therefore, measuring of Tg by mass spectrometry is the preferred method in TgAb positive patients.

 

The decision levels listed below 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 0.5 to 1.0 ng/mL per gram of remnant tissue, depending on the thyroid-stimulating hormone (TSH) level.

 

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 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.

Cautions

The test is most sensitive for detection of thyroid cancer recurrence when patients are off thyroid replacement long enough to have an elevated thyroid-stimulating hormone (TSH) prior to collecting the specimen. This test also can be used to follow patients with normal TSH; however, thyroglobulin (Tg) values from specimens with high TSH should not be compared with values with normal TSH, because TSH stimulation changes the baseline determinations.

 

Thyroglobulin autoantibodies (TgAb) may interfere with the measurement of Tg. All specimens are prescreened for TgAb and a comment appended to the report if they are present. Undetectable levels of Tg should be interpreted with caution if TgAb are present. A Tg antibody result of <4 IU/mL is unlikely to cause clinically significant Tg assay interference. It is recommended that the Tg result be reviewed for concordance with clinical presentation.

 

In rare cases, some individuals can develop antibodies to mouse or other animal antibodies (often referred to as human anti-mouse antibodies  or heterophile antibodies), which may cause interference in some immunoassays. Caution should be used in interpretation of results and the laboratory should be alerted if the result does not correlate with the clinical presentation.

 

Specimens with Tg concentrations greater than 250,000 ng/mL may "hook" and appear to have markedly lower levels.

 

Tg and TgAb values determined by different methodologies might vary significantly and cannot be directly compared with one another. Some patients might be antibody-positive by some methods and antibody-negative by others. Comparing values from different methods might lead to erroneous clinical interpretation.

Method Name

Immunoenzymatic Assay

Method Description

The Beckman Coulter Unicel DxI 800 is used for both thyroglobulin tumor marker and thyroglobulin antibody testing.

 

The Access Thyroglobulin (Tg) assay is a simultaneous 1-step immunoenzymatic (sandwich) assay. A sample is added to a reaction vessel, along with a biotinylated mixture of 4 monoclonal anti-Tg antibodies, streptavidin-coated paramagnetic particles, and monoclonal anti-Tg antibody alkaline phosphatase conjugate. The biotinylated antibodies and the serum Tg binds to the solid phase, while the conjugate antibody reacts with a different antigenic site on the Tg molecule. After incubation in a reaction vessel, materials bound to the solid phase are held in a magnetic field while unbound materials are washed away. Then, the chemiluminescent substrate Lumi-Phos 530 is added to the vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of Tg in the sample.(Instruction manual: Beckman Coulter Assay Manual, 2010)

 

The Access Thyroglobulin Antibody II assay (TgAb) is a sequential 2-step immunoenzymatic (sandwich) assay. A sample is added to a reaction vessel with paramagnetic particles coated with the thyroglobulin protein. The serum TgAb binds to the thyroglobulin. After incubation in a reaction vessel, materials bound to the solid phase are held in place by a magnetic field, while unbound materials are washed away.  The thyroglobulin-alkaline phosphatase conjugate is added and binds to the TgAb. After the second incubation, materials bound to the solid phase are held in place by a magnetic field, while unbound materials are washed away. Then, the chemiluminescent substrate, Lumi-Phos 530 is added to the reaction vessel and light generated by the reaction is measured with a luminometer. The light production is directly proportional to the concentration of thyroglobulin antibody in the sample.(Instruction manual: Thyroglobulin Antibody II Assay, Beckman Coulter, Inc., Fullerton, CA 2011)

CPT Code Information

84432

86800

LOINC Code Information

Test ID Test Order Name Order LOINC Value
HTG2 Thyroglobulin, Tumor Marker 57780-9

 

Result ID Test Result Name Result LOINC Value
TGAB2 Thyroglobulin Antibody, S 56536-6
HTGN2 Thyroglobulin, Tumor Marker, S 3013-0
HTG2I Thyroglobulin Interpretation 69053-7

Report Available

1 to 3 days

Test Classification

This test has been cleared, approved, or is exempt by the US 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.

Clinical Reference

1. Grebe SKG: Diagnosis and management of thyroid carcinoma: a focus on serum thyroglobulin. Exp Rev Endocrinol Metab. 2009;4(1):25-43. doi: 10.1586/17446651.4.1.25

2. Cooper DS, Doherty GM, Haugen BR, et al: Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Taskforce. Thyroid. 2009 Nov;19(11):1167-1214. doi: 10.1089/thy.2009.0110

3. Pacini F, Catagana MG, Brilli L, et al: Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010 May;21 Suppl 5:v214-9. doi: 10.1093/annonc/mdq190

4. National Comprehensive Cancer Network (NCCN) guidelines for treatment of cancer by site: version 2.2022: Thyroid Carcinoma. Accessed June 7, 2022. Available at - www.nccn.org/professionals/physician_gls/default.aspx#site

5. Tuttle, RM: Serum thyroglobulin in the management of differentiated thyroid cancer. Updated July 15, 2021. Accessed June 6, 2022. Available at www.uptodate.com/contents/differentiated-thyroid-cancer-role-of-serum-thyroglobulin

Forms

If not ordering electronically, complete, print, and send 1 of the following forms with the specimen:

-General Request (T239)

-Oncology Test Request (T729)