Why would free T4 (thyroxine) levels drop and free T3 (triiodothyronine) levels increase in a patient not on any medications?

Differential Diagnosis: Decreased Free T4 with Increased Free T3

This pattern of decreased free T4 with increased free T3 in a patient not on medications most commonly suggests either enhanced peripheral conversion of T4 to T3 (as seen in early Graves' disease or T3 thyrotoxicosis) or nonthyroidal illness syndrome with selective changes in deiodinase activity. 1, 2

Primary Diagnostic Considerations

Graves' Disease / T3 Thyrotoxicosis

• Approximately 5% of hyperthyroid patients present with selective T3 elevation (T3 thyrotoxicosis) where serum T4 may be normal or even decreased while T3 is markedly elevated. 3
• In Graves' disease, enhanced peripheral conversion of T4 to T3 can create a pattern where T3 rises disproportionately, potentially depleting T4 stores. 1
• Key diagnostic step: Check TSH immediately—if suppressed (low or undetectable), this confirms thyrotoxicosis. 3, 4
• Confirm with thyroid receptor antibodies (TRAb) or thyroid stimulating immunoglobulin (TSI) testing if clinical features suggest Graves' disease. 1, 4
• Clinical symptoms to assess: weight loss, palpitations, heat intolerance, hyperactivity, tremor. 4

Nonthyroidal Illness Syndrome (Euthyroid Sick Syndrome)

• In acute or chronic illness, altered deiodinase activity can decrease T4 while paradoxically maintaining or even increasing T3 in early phases, though typically T3 eventually falls. 5, 6
• The pattern you describe (low T4, high T3) is less common than the classic low T3 pattern, but can occur transiently in acute illness with enhanced type 1 deiodinase activity before the typical adaptive response sets in. 2, 6
• Critical distinguishing feature: TSH remains normal in nonthyroidal illness, whereas it is suppressed in hyperthyroidism. 5, 3
• Free T4 may be decreased due to impaired binding protein function and circulating inhibitors, while the T3/T4 ratio becomes elevated. 5, 2

Enhanced Peripheral T4 to T3 Conversion States

• Certain physiologic or pathologic states can upregulate type 1 deiodinase (DIO1), increasing conversion of T4 to T3. 7
• In low energy states or starvation, decreased total T3 and free T3 with decreased free T4 is typical, making your pattern less consistent with this etiology. 7
• Iron deficiency can impair T4 synthesis and hepatic conversion of T4 to T3, but typically results in low T3, not high T3. 7

Diagnostic Algorithm

Step 1: Measure TSH

• If TSH is suppressed (<0.1 mIU/L): Proceed with hyperthyroidism workup 4, 3

  • Check thyroid receptor antibodies (TRAb/TSI) 1, 4
  • Consider thyroid uptake scan if diagnosis unclear
  • Evaluate for clinical hyperthyroid symptoms 4

• If TSH is normal: Consider nonthyroidal illness or transient thyroid dysfunction 5, 2

  • Assess for acute or chronic systemic illness 5
  • Repeat thyroid function tests in 4-6 weeks to determine if transient 2
  • Check reverse T3 if available—elevated reverse T3 with low T3 supports nonthyroidal illness, though your pattern shows high T3 6

Step 2: Clinical Context Assessment

• Evaluate for hypermetabolic symptoms: tachycardia, weight loss, tremor, anxiety—these point toward thyrotoxicosis. 4, 2
• Assess for severe acute or chronic illness—this context supports nonthyroidal illness syndrome. 5, 2
• Check medication history again despite patient report—certain supplements or over-the-counter preparations can affect thyroid function 4

Critical Pitfalls to Avoid

• Do not assume euthyroidism based solely on one set of thyroid function tests when T4 and T3 are discordant—TSH is essential for interpretation. 3
• The pattern of isolated hyperthyroxinemia (high T4, low T3) is well-described in acute illness, but your reverse pattern (low T4, high T3) is less common and warrants careful evaluation for early hyperthyroidism. 2
• In critically ill patients, no single free T4 measurement method may accurately reflect thyroid status—clinical correlation is paramount. 5
• Unusual presentations with elevated T3 and normal or low TSH require endocrinology referral. 4

Most Likely Diagnosis Based on Pattern

Given the specific pattern of decreased free T4 with increased free T3 in an otherwise healthy patient not on medications, early T3 thyrotoxicosis or Graves' disease with preferential T3 production is the most likely diagnosis. 1, 3, 2 The TSH level will definitively distinguish between thyrotoxicosis (suppressed TSH) and a transient nonthyroidal illness pattern (normal TSH). 3