What is the best course of action for a patient with elevated Free Thyroxine (FT4) and normal Thyroid-Stimulating Hormone (TSH) levels?

Urgent Endocrinology Referral Required – This is NOT Primary Hypothyroidism

This patient has elevated FT4 (2.51, reference 0.78-2.19) with inappropriately normal TSH (2.7), which is pathognomonic for either thyroid hormone resistance syndrome or a TSH-secreting pituitary adenoma—not primary hypothyroidism requiring levothyroxine. 1

Critical First Step: Do Not Start Levothyroxine

• Levothyroxine therapy is contraindicated in this presentation and would be potentially harmful. 1
• Standard hypothyroidism treatment algorithms do not apply when TSH fails to suppress appropriately in the presence of elevated thyroid hormones. 1
• This biochemical pattern (elevated FT4 with non-suppressed TSH) requires immediate endocrinology referral rather than primary care management. 1

Confirm the Pattern is Real

• Repeat TSH, free T4, and free T3 within 2-4 weeks to confirm this pattern is persistent, as 30-60% of single abnormal values normalize on repeat testing. 1
• Measure free T3 specifically, as the current result shows slightly low FT3 (2.55, reference 2.77-5.27), which helps distinguish between different etiologies. 1
• Screen for assay interference by requesting the laboratory perform dilution studies or polyethylene glycol (PEG) precipitation, as heterophilic antibodies can cause spurious results in thyroid immunoassays. 2, 3

Assess for Tissue-Level Thyrotoxicosis

While awaiting endocrinology evaluation, assess whether the elevated FT4 is causing hyperthyroid symptoms:

• Check for tachycardia, tremor, heat intolerance, weight loss, and anxiety, which indicate tissue-level thyrotoxicosis despite the paradoxically normal TSH. 1
• Obtain an ECG to screen for atrial fibrillation, especially critical given prolonged TSH-driven hyperthyroidism increases cardiac arrhythmia risk, particularly in patients over 45 years. 1
• Evaluate cardiovascular status urgently if the patient has underlying heart disease, as even mild tissue-level hyperthyroidism can precipitate cardiac decompensation. 1

Differential Diagnosis to Consider

The two primary diagnoses that cause this pattern are:

• Thyroid hormone resistance syndrome: Genetic mutation in thyroid hormone receptors causing tissue resistance to thyroid hormone, requiring higher circulating levels to maintain euthyroidism. 1
• TSH-secreting pituitary adenoma (TSHoma): Autonomous TSH production from a pituitary tumor driving excessive thyroid hormone synthesis. 1

What the Endocrinologist Will Do

• Obtain pituitary MRI to evaluate for TSH-secreting adenoma, as macroadenomas or symptomatic microadenomas require transsphenoidal surgery as first-line treatment. 1
• Perform genetic testing for thyroid hormone receptor mutations if pituitary imaging is negative. 1
• Consider somatostatin analogs (octreotide or lanreotide) if surgery is contraindicated or incomplete for TSHoma. 1
• Radiation therapy may be offered for surgical failures or recurrence. 1

Common Pitfalls to Avoid

• Never assume this is subclinical or overt hypothyroidism based on TSH alone—the elevated FT4 with non-suppressed TSH excludes these diagnoses entirely. 1
• Do not delay endocrinology referral to "observe" or repeat testing multiple times, as tissue-level hyperthyroidism carries cardiovascular and bone risks. 1
• Avoid measuring only TSH in follow-up; always measure both TSH and free T4 together when monitoring this condition. 4
• If the patient is a woman of childbearing age, specialized management during pregnancy will be required, as fetal thyroid development may be affected differently than maternal tissues. 1

Additional Monitoring if Chronic Hyperthyroidism Suspected

• Check bone density if chronic hyperthyroidism is suspected, as prolonged elevation of thyroid hormones accelerates bone loss. 1
• Monitor for development of atrial fibrillation with serial ECGs, especially in elderly patients. 1