When to Test for Thyroxine Binding Globulin (TBG)
TBG testing is indicated when total T4 levels are discordant with the clinical picture and free T4 levels—specifically when a patient has elevated or low total T4 but normal free T4 and TSH, suggesting a binding protein abnormality rather than true thyroid dysfunction.
Primary Clinical Scenarios Requiring TBG Testing
Discordant Thyroid Function Tests
- Measure TBG when total T4 is elevated but the patient lacks clinical signs of hyperthyroidism and has normal free T4 and TSH levels 1, 2
- TBG testing prevents inappropriate treatment for presumed thyrotoxicosis—in one series, 3 of 4 patients with TBG excess had received unnecessary antithyroid therapy 2
- Conversely, test TBG when total T4 is low in a clinically hyperthyroid patient with elevated free T4, as this pattern suggests TBG deficiency coexisting with true thyroid disease 1
Hyperthyroxinemia with Normal TSH
- TBG excess occurs in approximately 0.45% of hospital populations and produces total T4 levels comparable to clinical thyrotoxicosis 2
- Total T3 is frequently elevated (though less than in true thyrotoxicosis), which can further confuse the clinical picture 3, 2
- In neonatal screening programs, persistent hyperthyroxinemia with normal free T4 and TSH warrants TBG measurement 3
Specific Patient Populations
Neonates and Infants
- TBG testing is appropriate when neonatal screening reveals elevated total T4 but subsequent testing shows normal free T4 (1.99 ng/dL, range 0.8-2.1) and normal TSH (4.54 mIU/L, range 0.5-6.5) 3
- TBG excess in infants typically shows levels 2-3 times normal (48-68 mg/L versus normal 14-36 mg/L) with consistently elevated total T3 and T4 but normal free hormones 3
Patients with Coexisting Thyroid Disease
- When Graves' disease is suspected but total T4 is unexpectedly normal or low despite elevated free T4 and suppressed TSH, measure TBG to identify complete TBG deficiency 1
- This prevents unnecessary additional testing and clarifies the discordant laboratory pattern 1
When TBG Testing Is NOT Indicated
Thyroid Cancer Surveillance
- TBG measurement has no role in preoperative staging or initial diagnosis of thyroid cancer 4
- In thyroid cancer follow-up, anti-thyroglobulin antibodies (not TBG) are measured solely as interference markers that invalidate standard thyroglobulin measurements 4
Routine Thyroid Screening
- The USPSTF found insufficient evidence for routine thyroid screening in asymptomatic adults, making TBG testing even less justified in this context 5
- Standard thyroid assessment relies on TSH with reflex to free T4, not TBG 5
Clinical Pitfalls to Avoid
Common Diagnostic Errors
- Do not treat elevated total T4 as thyrotoxicosis without confirming elevated free T4 and suppressed TSH—TBG excess is a benign condition requiring no therapy 3, 2
- Do not assume normal total T4 excludes hyperthyroidism in patients with clinical thyrotoxicosis; TBG deficiency can mask the diagnosis 1
- The TRH stimulation test is useful for evaluating thyroid status when TBG abnormalities create diagnostic uncertainty 2
Laboratory Interpretation
- TBG assays that measure thyroxine binding capacity of all proteins (not just TBG-specific immunoassays) may provide more clinically useful free T4 index calculations 6
- A single T4:TBG reference range is problematic—it produces false positives for hyperthyroidism at low TBG levels and false negatives at high TBG levels 7
- Report results graphically or use empirical reference ranges specific to the patient's TBG level 7
Practical Algorithm
- Identify discordant pattern: Total T4 abnormal but free T4 and TSH normal
- Assess clinical context: Presence or absence of thyroid symptoms
- Order TBG level: If pattern suggests binding protein abnormality
- Interpret results:
- TBG excess: Total T4 elevated, free T4 normal, TBG >36 mg/L
- TBG deficiency: Total T4 low, free T4 normal, TBG undetectable or very low
- Avoid treatment: These are benign conditions requiring monitoring only 3, 2