What does a high Thyroid hormone (T4) level with a normal Thyroid-stimulating hormone (TSH) level indicate?

Normal TSH with High T4: Diagnostic Approach

A normal TSH with elevated T4 most commonly indicates either a thyroid hormone binding protein abnormality (such as familial dysalbuminemic hyperthyroxinemia), assay interference, or rarely, central hyperthyroidism or thyroid hormone resistance—and the key is to confirm the finding with repeat testing and assess the patient's clinical thyroid status.

Initial Clinical Assessment

The first step is determining whether the patient is clinically euthyroid or thyrotoxic:

• If clinically euthyroid with normal TSH, this pattern suggests "euthyroid hyperthyroxinemia" rather than true hyperthyroidism 1
• If clinically thyrotoxic with non-suppressed TSH, consider the rare entities of central hyperthyroidism or thyroid hormone resistance 2, 3

Confirm the Laboratory Findings

Repeat thyroid function tests over a 3-6 month interval to confirm persistent abnormality, as recommended for all thyroid dysfunction screening 4

• Measure both free T4 and total T4 to help differentiate binding protein abnormalities from true thyroid dysfunction 1
• Obtain T3 levels, as normal T3 with elevated T4 suggests a binding protein issue rather than hyperthyroidism 1

Differential Diagnosis Algorithm

For Euthyroid Patients (Most Common Scenario):

1. Familial Dysalbuminemic Hyperthyroxinemia (FDH)

• Characterized by elevated total T4, elevated or normal free T4, normal T3, and normal TSH in clinically euthyroid patients 1
• Caused by variant serum albumin with preferential T4 binding 1
• Autosomal dominant inheritance—obtain family history 1
• Confirm by demonstrating increased T4 binding to serum albumin 1

2. Other Binding Protein Abnormalities

• Increased thyroid-binding globulin (TBG) or other quantitative/qualitative changes in thyroid hormone-binding proteins 1
• Drug effects or acute illness can also cause euthyroid hyperthyroxinemia 1

3. Assay Interference

• TSH values can be affected by technical issues with TSH assay, abnormal TSH isoforms, or heterophilic antibodies 5
• Consider this especially if results don't fit clinical picture 5

For Thyrotoxic Patients (Rare Scenarios):

1. TSH-Producing Pituitary Adenoma (TSHoma)

• Presents with thyrotoxicosis, elevated free T4 and T3, and non-suppressed TSH 2
• Measure serum alpha-subunit (typically elevated) 2
• Perform TRH stimulation test (blunted or absent TSH response) 2
• Obtain pituitary MRI to identify adenoma 2

2. Thyroid Hormone Resistance (PRTH)

• Pituitary resistance to thyroid hormone with normal peripheral tissue sensitivity 2, 3
• Patients experience peripheral thyrotoxic effects despite elevated TSH 2
• Goiter is typically present 3
• TSH increases following TRH administration (unlike TSHoma) 3
• Caused by mutations in thyroid hormone receptor beta gene 2
• Nuclear T3 receptor studies may show abnormalities 3

3. TSH Receptor Resistance

• Elevated TSH with variable thyroid hormone levels (can be normal to high) 6
• Caused by TSH receptor gene mutations 6
• May present without goiter, distinguishing it from other causes 6

Critical Pitfalls to Avoid

Do not treat euthyroid hyperthyroxinemia as hyperthyroidism—this is the most common error and can lead to unnecessary and harmful therapy 1, 3:

• Three of the patients in one case series were inappropriately treated for presumed Graves' disease when they actually had thyroid hormone resistance 3
• Clinical euthyroidism with normal TSH definitively excludes thyrotoxicosis 1

Do not confuse these conditions with primary hyperthyroidism, which always presents with suppressed (undetectable) TSH 2

Recommended Diagnostic Workup

For confirmed normal TSH with elevated T4:

1. Assess clinical thyroid status (symptoms, heart rate, tremor, weight changes) 1
2. Measure T3 levels—normal T3 strongly suggests binding protein abnormality 1
3. Check thyroid antibodies (TPO, thyroglobulin) to assess for autoimmune disease 5
4. Obtain family history for thyroid disorders or similar laboratory patterns 1
5. If clinically thyrotoxic: measure alpha-subunit, perform TRH stimulation test, and obtain pituitary MRI 2
6. If FDH suspected: demonstrate increased T4 binding to albumin and screen family members 1

The key distinguishing feature is that true hyperthyroidism always suppresses TSH to undetectable levels, so a normal TSH definitively rules out primary hyperthyroidism and indicates either a binding protein issue, assay problem, or rare central disorder 1, 2.