What to do with a patient with normal Thyroid-Stimulating Hormone (TSH) and elevated Triiodothyronine (T3) and Thyroxine (T4) levels?

Immediate Evaluation for Thyroid Hormone Resistance or Assay Interference

This pattern of normal TSH with elevated T3 and T4 is biochemically abnormal and requires urgent investigation to distinguish between thyroid hormone resistance syndrome, TSH-secreting pituitary adenoma, assay interference, or laboratory error—not routine thyroid management.

Critical First Steps: Rule Out Laboratory Error and Assay Interference

• Repeat thyroid function tests immediately using a different laboratory platform or assay method, as macro-TSH, heterophile antibodies, or biotin interference can cause falsely discordant results 1
• Confirm the TSH measurement is not falsely elevated by macro-TSH (TSH-immunoglobulin complex), which occurs particularly in autoimmune thyroid disorders and can show remarkably elevated TSH with normal free thyroid hormones 1
• If macro-TSH is suspected, perform polyethylene glycol (PEG) precipitation testing—recovery <40% suggests macro-TSH interference 1
• Check for human antimouse IgG antibody (HAMA) interference, which can produce spuriously elevated hormone measurements 1

Differential Diagnosis: What This Pattern Actually Represents

Most Likely: Thyroid Hormone Resistance Syndrome

• Generalized resistance to thyroid hormone presents with elevated T4 and T3, inappropriately normal or elevated TSH, and clinical euthyroidism or mild symptoms 2
• The hallmark is failure of negative feedback—elevated thyroid hormones do not suppress TSH as expected 2
• Patients typically have goiter, normal or mildly elevated metabolic rate, and normal testosterone-estradiol binding globulin despite high thyroid hormone levels 2

Second Possibility: TSH-Secreting Pituitary Adenoma

• TSH-secreting adenomas produce autonomous TSH secretion despite elevated thyroid hormones 2
• Distinguished from resistance syndrome by measuring serum alpha-subunit (elevated in adenomas) and pituitary imaging 2
• Hyperresponsiveness of TSH to TRH stimulation suggests pituitary pathology 2

Third Possibility: Assay Artifact

• Laboratory error or assay interference is common and must be excluded first 1
• Different immunoassay platforms can produce varying results, making direct comparison problematic 3

Diagnostic Algorithm

Step 1: Confirm the abnormality

• Repeat TSH, free T4, and free T3 using a different assay platform within 1-2 weeks 1
• If results remain discordant, proceed to Step 2

Step 2: Assess clinical thyroid status

• Measure basal metabolic rate or resting energy expenditure to determine true metabolic state 2
• Check testosterone-estradiol binding globulin (elevated in true hyperthyroidism, normal in resistance) 2
• Assess for clinical signs: goiter size, heart rate, tremor, weight, temperature intolerance 2

Step 3: Distinguish pituitary adenoma from resistance

• Measure serum alpha-subunit concentration (elevated in TSH-secreting adenomas, normal in resistance) 2
• Obtain pituitary MRI with gadolinium contrast 2
• Perform TRH stimulation test—exaggerated TSH response suggests adenoma 2

Step 4: If resistance syndrome confirmed

• No treatment is typically required if patient is clinically euthyroid, as the elevated thyroid hormones represent the patient's compensated state 2
• If symptomatic hyperthyroidism develops, bromocriptine 2.5-10 mg daily can decrease TSH secretion and reduce goiter size while maintaining clinical euthyroidism 2
• Never treat with antithyroid drugs (methimazole) or radioactive iodine, as this will worsen the condition by removing the compensatory thyroid hormone elevation 4, 2

Critical Pitfalls to Avoid

• Do not diagnose hyperthyroidism based on elevated T3/T4 alone when TSH is normal—this violates basic thyroid physiology where elevated thyroid hormones should suppress TSH 5, 2
• Do not initiate antithyroid medication without confirming true hyperthyroidism, as methimazole only inhibits new thyroid hormone synthesis and would be inappropriate for resistance syndromes 4
• Do not assume laboratory values are correct without verification—up to 5% of thyroid function tests may show interference from antibodies or other factors 1
• Do not use TSH alone to guide therapy in this scenario—the normal TSH with elevated thyroid hormones indicates the feedback loop is disrupted 6, 2

Monitoring Strategy Pending Diagnosis

• Recheck thyroid function tests in 2-4 weeks using a different laboratory 1
• Measure free T4 and free T3 directly (not calculated indices) to confirm elevation 5, 7
• Assess for cardiac complications if truly hyperthyroid: obtain ECG, check for atrial fibrillation 8
• If patient has cardiac disease or atrial fibrillation, consider more urgent evaluation within days rather than weeks 8

When to Refer to Endocrinology Immediately

• All cases with confirmed discordant thyroid function tests (normal TSH with elevated T3/T4) require endocrinology consultation 2
• Urgent referral if pituitary adenoma suspected based on alpha-subunit elevation or visual field defects 2
• Immediate referral if patient develops symptomatic hyperthyroidism with tachycardia, weight loss, or cardiac complications 8, 2