What are the next steps for a patient with normal Thyroid-Stimulating Hormone (TSH) and low free Thyroxine (T4)?

Next Steps for Normal TSH and Low Free T4

For a patient with normal TSH and low free T4, the next step should be to evaluate for central hypothyroidism by testing morning ACTH, cortisol, and other pituitary hormones, and obtaining an MRI of the pituitary to rule out hypophysitis or other pituitary pathology. 1

Diagnostic Algorithm

1. Initial Assessment

• Confirm laboratory values
  • Verify low free T4 with normal TSH
  • Rule out laboratory error or assay interference
• Evaluate for symptoms of hypothyroidism:
  • Fatigue, weight gain, hair loss, cold intolerance, constipation, depression 1

2. Differential Diagnosis

Central Hypothyroidism (Most Likely)

Central hypothyroidism presents with low free T4 and normal/low TSH due to pituitary or hypothalamic dysfunction. This pattern is particularly concerning for:

• Hypophysitis: Especially in patients on immune checkpoint inhibitors 1
• Other pituitary disorders: Tumors, infiltrative disease, infarction
• Hypothalamic dysfunction

Non-Thyroidal Illness Syndrome

• Seen in critically ill patients or those with severe systemic illness 2
• Represents an adaptive response rather than true hypothyroidism
• TSH typically normal with low T3 and sometimes low T4

Medication Effects

• Certain drugs can affect thyroid hormone binding or metabolism
• Examples include glucocorticoids, dopamine, amiodarone, biotin

3. Recommended Workup

1. Morning Pituitary Panel (preferably around 8 am) 1:

   • ACTH and cortisol (or 1 mcg cosyntropin stimulation test)
   • FSH/LH
   • Testosterone (men) or estradiol (women)
   • Prolactin

2. MRI of the pituitary with dedicated pituitary cuts 1

   • Look for enlargement, heterogeneous enhancement, increased height of gland
   • Should be done prior to starting steroids if hypophysitis is suspected

3. Additional thyroid testing:

   • Anti-TPO antibodies to evaluate for thyroiditis 1
   • T3 levels if clinically indicated

4. Management Based on Findings

If Central Hypothyroidism is Confirmed:

• Start hormone replacement therapy:
  • For combined adrenal insufficiency and hypothyroidism: Always start steroids first before thyroid hormone to avoid precipitating adrenal crisis 1
  • Hydrocortisone 15 mg AM, 5 mg at 3 PM (approximately 10 mg/m²) 1
  • After steroid initiation, start levothyroxine at appropriate dose 3

For Secondary/Tertiary Hypothyroidism:

• Dosing of levothyroxine should be based on clinical response and free T4 levels, not TSH 3
• Target free T4 to the upper half of normal range 3
• Initial dose typically 1.6 mcg/kg/day in otherwise healthy adults, but start lower (25-50 mcg) in elderly or those with cardiac disease 1, 3
• Monitor free T4 every 6-8 weeks until stable 1

Important Considerations

• TSH is not reliable for monitoring therapy in central hypothyroidism 3, 4
• If hypophysitis is suspected (especially in patients on immune checkpoint inhibitors), endocrinology consultation is strongly recommended 1
• Patients with adrenal insufficiency should be instructed to obtain a medical alert bracelet 1
• The prevalence of low free T4 with normal TSH is approximately 3.3% of patients having thyroid function tests 5
• Full evaluation of medical records often reveals potential causes that may have been missed initially 5

Pitfalls to Avoid

• Do not start thyroid hormone before ruling out adrenal insufficiency - this can precipitate adrenal crisis 1
• Do not rely on TSH to monitor treatment in central hypothyroidism - use free T4 levels instead 3, 4
• Do not assume non-thyroidal illness without proper evaluation, especially in non-critically ill patients 2
• Do not miss the diagnosis of hypophysitis in patients on immune checkpoint inhibitors, as this is a known complication 1