What is the workup for a patient with low free Thyroxine (T4) and normal Thyroid-stimulating hormone (TSH) levels?

Workup for Low Free T4 with Normal TSH

A patient with low free T4 and normal TSH should undergo evaluation for central hypothyroidism, which requires a complete anterior pituitary hormone assessment and MRI of the sella turcica. 1

Initial Evaluation

1. Complete anterior pituitary hormone assessment:

   • Early morning ACTH and cortisol (crucial to rule out adrenal insufficiency before thyroid replacement)
   • Gonadotropins (LH, FSH)
   • Growth hormone and IGF-1
   • Repeat thyroid function tests to confirm findings

2. Imaging:

   • MRI of the sella turcica to evaluate for pituitary enlargement, stalk thickening, or other structural abnormalities

Differential Diagnosis

The pattern of normal TSH with low free T4 suggests several possible etiologies:

1. Central (secondary) hypothyroidism 1

   • Pituitary adenoma
   • History of pituitary surgery or radiation
   • Infiltrative diseases
   • Traumatic brain injury
   • Immune checkpoint inhibitor therapy (hypophysitis)
   • Sheehan syndrome
   • Genetic disorders

2. Non-thyroidal illness syndrome 2

   • Severe acute or chronic illness can cause decreased T4 to T3 conversion
   • Usually an adaptive response that doesn't require treatment

3. Laboratory interference 3

   • Heterophile antibodies
   • Thyroxine-binding globulin (TBG) deficiency
   • Medication effects

4. Assay variability 4

   • Consider repeating tests in a different laboratory

Management Algorithm

1. Rule out adrenal insufficiency first 1, 5

   • Critical step before initiating thyroid replacement
   • Initiating thyroid replacement without addressing adrenal insufficiency can precipitate an adrenal crisis

2. If central hypothyroidism is confirmed:

   • Start levothyroxine at 1.6 μg/kg/day for adults
   • For elderly or those with cardiac disease, start at 25 μg daily
   • Alternative: Desiccated thyroid extract (DTE) 25-50 mg daily for elderly/cardiac patients, or 60-65 mg (1 grain) for younger patients

3. If non-thyroidal illness is suspected:

   • Address the underlying illness
   • Thyroid replacement is generally not indicated as this represents an adaptive response 2

4. If laboratory interference is suspected:

   • Repeat testing with dilution
   • Check TBG levels
   • Consider changing laboratories or assay methods

Monitoring

• For central hypothyroidism: 1

  • Free T4 levels should guide dose adjustments (not TSH)
  • Monitor 6-8 weeks after initiation or dose adjustment
  • Once stable, monitor annually

• Special considerations: 5

  • If patient has diabetes: Monitor glucose closely as thyroid replacement may increase insulin or oral hypoglycemic requirements
  • If patient is on anticoagulants: Monitor prothrombin time frequently as thyroid hormones increase catabolism of vitamin K-dependent clotting factors
  • If patient is on estrogen therapy: May need to increase thyroid dose due to increased TBG

Common Pitfalls to Avoid

1. Relying on TSH alone for monitoring central hypothyroidism

   • Free T4 is the primary monitoring parameter in central hypothyroidism 1, 6

2. Initiating thyroid replacement before ruling out adrenal insufficiency

   • Can precipitate adrenal crisis 1, 5

3. Assuming all cases of low T4 with normal TSH require treatment

   • Non-thyroidal illness syndrome is often an adaptive response and doesn't require thyroid replacement 2

4. Overlooking medication interactions

   • Many medications can affect thyroid hormone levels and binding proteins 5

5. Missing laboratory interferences

   • Heterophile antibodies and TBG abnormalities can cause misleading results 3

By following this systematic approach, you can properly identify the cause of low free T4 with normal TSH and implement appropriate management strategies.