Thyroglobulin (Tg) Measurement

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Serum Tg Reference Values

Serum Tg concentrations are log-normally distributed in euthyroid individuals. Values tend to be slightly higher in women, but gender-related reference ranges are unnecessary.[335] Cigarette smoking is a factor associated with goiter and higher serum Tg values.[336] Tg reference ranges are geographically sensitive, since serum Tg is influenced by iodide availability and intake.[337,338] Subject selection for the normal cohort for Tg reference range determinations should have the following exclusion criteria:

  • Goiter

  • Cigarette smoking

  • Personal or family history of thyroid disease

  • Presence of thyroid autoantibodies (TgAb and/or TPOAb)

  • Serum TSH < 0.5 mIU/L or >2.0 mIU/L

As indicated by Guideline 48, the Tg reference interval cited on laboratory reports does not apply to patients who have had thyroid surgery! In the first few weeks after surgery, the serum Tg will be determined by the completeness of the surgery, the degree of leakage of Tg from the surgical margins, and most importantly whether thyroid hormone has been given to prevent the expected rise in TSH. In fact, the serum TSH concentration is such a powerful modulator of the serum Tg level that it is usually necessary to know the TSH status of the patient before assessing the significance of any serum Tg measurement.

In the early weeks following thyroidectomy, serum Tg concentrations typically fall with a half-life approximating 2-4 days, when thyroid hormone administration prevents TSH from rising.[340,341] In this setting, the relationship between the pre-operative and 6-8 week post-operative serum Tg values can provide information that could influence the treatment plan. During long-term monitoring, serum Tg concentrations measured on and off L-T4 treatment (low or high TSH, respectively) provide different information. The pattern of change in serum Tg values (on L-T4 treatment) is a better indicator of a change in tumor burden than any single serum Tg value.[122] The serum Tg concentration during L-T4 treatment is a more stable indicator of tumor mass than a serum Tg measured when the TSH is high (L-T4 withdrawal or rhTSH administration) prior to a radioiodine (RAI) scan. This is because the magnitude of the TSH-stimulated serum Tg elevation is influenced by the extent and chronicity of the TSH elevation, which can vary from scan to scan. However, as shown in Figure 6, because TSH usually stimulates serum Tg more than 10-fold, TSH-stimulated serum Tg measurements are more sensitive for detecting disease confined to the neck, than serum Tg levels measured during TSH suppression.[308,309] The magnitude of the TSH-stimulated serum Tg response provides a gauge of the TSH sensitivity of the tumor. Poorly differentiated metastatic tumors that are RAI-scan negative have blunted (less than three-fold) TSH-stimulated serum Tg responses.[310]

Guideline 48. Serum Tg Normal Reference Intervals

  • Tg reference ranges should be determined locally because serum Tg concentrations are influenced by iodide intake:

    Countries with adequate iodide intake: The serum Tg reference interval for a TgAb-negative euthyroid population using CRM-457-standards approximates 3 to 40 µg/L (ng/ml).

    Countries manifesting iodide deficiency: The population mean Tg value and the upper Tg reference limit may be elevated relative to the degree of iodide deficiency.

  • Laboratories should validate their Tg normal reference interval independent of the manufacturer.

  • Tg reference ranges should be established from the log transformed values of 120 normal, non-smoking, euthyroid (TSH 0.5 to 2.0 mIU/L) subjects less than 40 years of age with no personal or family history of thyroid disease and with no evidence of TgAb or TPOAb.

  • It is misleading to cite the normal euthyroid reference range when reporting serum Tg values for thyroidectomized DTC patients. Reference values should be related to the euthyroid reference limits for the method, the thyroid mass and TSH status.

For example, the reference ranges below would be appropriate for a Tg method with a euthyroid reference range of 3-40 µg/L (ng/ml):

Tg µg/L (ng/ml) Condition
3 - 40 Normal thyroid gland reference (TSH 0.4-4.0 mIU/L)
1.5 - 20 Normal thyroid gland reference (TSH <0.1 mIU/L)
< 10 Thyroid lobectomy (TSH < 0.1 mIU/L)
< 2 Near-total thyroidectomy (TSH < 0.1 mIU/L)