Why can Thyroid-Stimulating Hormone (TSH) be normal while Thyroxine (T4) is low?

Normal TSH with Low T4: Causes and Clinical Significance

A normal TSH with low T4 most commonly indicates central (secondary) hypothyroidism due to pituitary or hypothalamic dysfunction, or may represent non-thyroidal illness syndrome in acutely ill patients. This pattern requires careful evaluation as it contradicts the typical feedback relationship between TSH and thyroid hormones.

Potential Causes

1. Central (Secondary) Hypothyroidism

• Pituitary dysfunction (hypopituitarism)
• Hypothalamic dysfunction
• Pituitary tumors or infiltrative disease
• Hypophysitis (particularly in patients on immune checkpoint inhibitors)

2. Non-Thyroidal Illness Syndrome (NTIS)

• Common in critically ill patients
• Represents an adaptive change to conserve energy during severe illness 1
• Characterized by decreased T3 production from T4 and impaired binding of thyroid hormones

3. Medication Effects

• Certain drugs affecting thyroid hormone metabolism
• Iodine-containing contrast agents from CT scans can impact thyroid function tests 2

4. Early Recovery from Hyperthyroidism

• During treatment of hyperthyroidism, TSH may normalize before T4 levels recover

5. Laboratory Interference

• Assay interference affecting T4 measurement
• Abnormal thyroid binding proteins

Diagnostic Approach

When encountering normal TSH with low T4:

1. Check for pituitary dysfunction:

   • Measure 9 AM cortisol 2
   • Consider evaluating other pituitary hormones
   • Brain MRI may be indicated to evaluate the pituitary gland

2. Assess for non-thyroidal illness:

   • Review for acute or chronic severe illness
   • Check albumin and other markers of nutritional status

3. Medication review:

   • Identify medications that may affect thyroid function or testing

4. Repeat testing:

   • If no symptoms, repeat thyroid function tests at next clinical visit 2
   • For patients on immune checkpoint inhibitors, monitor thyroid function every cycle 2

Management Considerations

Management depends on the underlying cause:

• For central hypothyroidism:

  • Levothyroxine replacement (typically 1.6 mcg/kg/day) 3, 4
  • Monitor free T4 levels rather than TSH for dose adjustment 4
  • Maintain free T4 in the upper half of the normal range 4
  • Rule out adrenal insufficiency before starting thyroid replacement

• For non-thyroidal illness:

  • Generally no thyroid hormone replacement is indicated 1
  • Focus on treating the underlying illness
  • Re-evaluate thyroid function after recovery

• For immune checkpoint inhibitor-related thyroid dysfunction:

  • Monitor thyroid function tests regularly 2
  • Consider endocrinology consultation for persistent abnormalities

Clinical Significance

The prevalence of normal TSH with aberrant free T4 is approximately 3.3% of all thyroid function tests, with decreased free T4 being more common than increased free T4 5. This pattern requires thorough investigation as it may indicate serious underlying conditions.

When evaluating this pattern, it's important to recognize that while TSH is typically considered the most sensitive marker of thyroid function, there are specific clinical scenarios where the TSH-T4 relationship does not follow the expected pattern 6.

Monitoring Recommendations

• For patients with confirmed central hypothyroidism on levothyroxine:

  • Monitor free T4 levels 6-8 weeks after initiating therapy 3
  • Adjust dose to maintain free T4 in the upper half of normal range 4
  • Once stable, evaluate clinical and biochemical response every 6-12 months 4

• For patients with non-thyroidal illness:

  • Repeat thyroid function tests after recovery from acute illness

Remember that thorough investigation of the underlying cause is essential for proper management of patients with normal TSH and low T4.