What is the approach to managing a patient with decreased Triiodothyronine (T3) and Thyroxine (T4) levels but normal Thyroid-Stimulating Hormone (TSH) levels?

Approach to Decreased T3 and T4 with Normal TSH

This pattern of low T3 and low T4 with normal TSH indicates central hypothyroidism (secondary or tertiary hypothyroidism due to pituitary or hypothalamic dysfunction), which requires immediate levothyroxine replacement guided by free T4 levels rather than TSH. 1

Critical Diagnostic Distinction

The combination of low free T4 with inappropriately normal or low TSH definitively indicates central hypothyroidism rather than primary thyroid disease. 1 This is fundamentally different from primary hypothyroidism where TSH would be elevated. In central hypothyroidism, the pituitary fails to produce adequate TSH or the hypothalamus fails to produce adequate TRH, meaning TSH cannot be used as a reliable screening or monitoring test. 1

Immediate Pre-Treatment Evaluation (CRITICAL)

Before initiating any thyroid hormone replacement, you must rule out concurrent adrenal insufficiency, as starting thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis. 1 This is non-negotiable.

Required Tests Before Treatment:

• Morning ACTH and cortisol levels or 1 mcg cosyntropin stimulation test to assess adrenal function 1
• Free T4 by equilibrium dialysis for accurate baseline measurement 1
• MRI of the sella with pituitary cuts to evaluate for hypophysitis, pituitary enlargement, stalk thickening, or suprasellar masses 1
• FSH, LH, and gonadal hormones to assess for panhypopituitarism (occurs in ~50% of hypophysitis cases) 1

Treatment Sequence:

If both adrenal insufficiency and hypothyroidism are confirmed, start corticosteroids at least 1 week before initiating levothyroxine. 1 Failure to do this can precipitate adrenal crisis as thyroid hormone increases cortisol metabolism. 2

Alternative Diagnosis: Nonthyroidal Illness Syndrome (Euthyroid Sick Syndrome)

If the patient has acute severe illness, hospitalization, or recent major surgery, consider nonthyroidal illness syndrome (NTIS) as an alternative diagnosis. 3, 4, 5

Characteristics of NTIS:

• Low T3 syndrome is the most common pattern, occurring in essentially all severe systemic illnesses 3, 5
• Combined low T3 and low T4 occurs in more severe/prolonged illness 3, 4
• TSH remains normal or low despite low thyroid hormones 3, 5
• Reverse T3 is typically elevated 3, 6
• Mechanisms include decreased type 1 5'-deiodinase activity, decreased tissue uptake of T4, decreased serum binding, and suppressed hypothalamic TRH expression in prolonged illness 3, 4

Management of NTIS:

Do NOT treat NTIS with levothyroxine during acute illness. 3, 5 This represents a physiological adaptation to severe illness. Treatment with T4 has yielded little improvement, and the mortality rate is inversely correlated with serum T4 concentration. 5 Recheck thyroid function 4-6 weeks after recovery from the acute illness to determine if true hypothyroidism exists. 2

Levothyroxine Dosing for Confirmed Central Hypothyroidism

Initial Dosing:

• For patients <70 years without cardiac disease: Start levothyroxine 1.6 mcg/kg/day 1
• For patients >70 years or with cardiac disease: Start 25-50 mcg/day with gradual titration, monitoring for cardiac arrhythmias 1

Dose Adjustments:

• Adjust in 12.5-25 mcg increments based on free T4 levels 1
• Wait 6-8 weeks between adjustments to reach steady state 1

Monitoring Protocol

Monitor free T4 levels, NOT TSH, to guide therapy in central hypothyroidism. 1 TSH is unreliable in this condition.

Monitoring Schedule:

• Recheck free T4 6-8 weeks after dose adjustment, targeting approximately 14-19 pmol/L 1
• Once stable, monitor free T4 every 6-12 months 1
• Annual monitoring of other pituitary hormones may be warranted depending on etiology 1

Common Pitfalls to Avoid

• Never rely on TSH to diagnose or monitor central hypothyroidism - TSH will remain inappropriately normal or low despite inadequate thyroid hormone levels 1
• Never start thyroid hormone before ruling out adrenal insufficiency in suspected central hypothyroidism or hypophysitis 2, 1
• Do not treat nonthyroidal illness syndrome during acute illness - wait for recovery and retest 3, 5
• Avoid missing central hypothyroidism by checking free T4 alongside TSH in patients with pituitary disease or symptoms despite normal TSH 2

Long-Term Considerations

Patients with central hypothyroidism typically require lifelong hormone replacement. 1 Ensure patients with confirmed adrenal insufficiency obtain and carry a medical alert bracelet. 1