Do I start levothyroxine (T4) if Thyroid-Stimulating Hormone (TSH) is normal and free thyroxine (FT4) is low?

Normal TSH with Low Free T4: When to Start Levothyroxine

Do not start levothyroxine for isolated low free T4 with normal TSH without first ruling out central hypothyroidism (hypophysitis) or laboratory error. This pattern is atypical for primary hypothyroidism and requires further investigation before treatment.

Critical Diagnostic Considerations

The combination of normal TSH with low free T4 suggests central hypothyroidism rather than primary thyroid dysfunction, which requires a fundamentally different diagnostic and therapeutic approach 1.

Immediate Evaluation Required

• Measure morning ACTH and cortisol levels (around 8 AM) to assess for concurrent adrenal insufficiency, as central hypothyroidism often occurs with hypopituitarism 1.
• Obtain MRI of the sella with pituitary cuts to evaluate for pituitary pathology, particularly if using immune checkpoint inhibitors or if headache is present 1.
• Check additional pituitary hormones including FSH, LH, and gonadal hormones (testosterone in men, estradiol in women) to assess for panhypopituitarism 1.
• Repeat thyroid function tests to confirm the pattern, as 30-60% of abnormal results normalize on repeat testing 2, 3.

Common Clinical Scenarios

Hypophysitis (especially with immunotherapy): This presents with low TSH or low-normal TSH alongside low free T4, affecting >90% of patients with this condition 1. Headache occurs in 85% and fatigue in 66% of cases 1.

Laboratory interference or assay variability: Free T4 assays can be affected by binding proteins, medications, or technical factors that may produce spuriously low results 4.

Treatment Algorithm

If Central Hypothyroidism is Confirmed

Before starting levothyroxine, you must rule out and treat adrenal insufficiency first - starting thyroid hormone before corticosteroids can precipitate life-threatening adrenal crisis 1, 5.

1. Start physiologic dose hydrocortisone (15-25 mg daily in divided doses) if ACTH/cortisol deficiency is present 1.
2. Wait 24-48 hours after starting steroids before initiating thyroid hormone replacement 1.
3. Begin levothyroxine at standard replacement doses (1.6 mcg/kg/day for patients <70 years without cardiac disease, or 25-50 mcg/day for elderly or cardiac patients) 5, 3.
4. Monitor with free T4 levels rather than TSH since TSH cannot be used to guide dosing in central hypothyroidism 1.

If Primary Hypothyroidism is Suspected Despite Normal TSH

This scenario is extremely rare. Primary hypothyroidism characteristically presents with elevated TSH and low free T4 5, 2, 3. A normal TSH essentially rules out primary hypothyroidism 3.

• Do not start levothyroxine based on isolated low free T4 with normal TSH without confirming the diagnosis 2.
• Consider non-thyroidal illness which can transiently lower free T4 while TSH remains normal, and typically resolves without treatment 5.

Key Pitfalls to Avoid

• Never start thyroid hormone before ruling out adrenal insufficiency in patients with suspected central hypothyroidism - this is the most critical error and can be fatal 1, 5.
• Do not use TSH alone to guide treatment decisions when central hypothyroidism is suspected, as TSH will be inappropriately normal or low 1.
• Avoid treating based on a single abnormal test - confirm the pattern with repeat testing before committing to lifelong therapy 2, 3.
• Do not assume primary hypothyroidism when the TSH is normal - this pattern demands investigation for pituitary or hypothalamic disease 1.

Monitoring After Treatment Initiation

• Recheck free T4 (not TSH) in 6-8 weeks after starting levothyroxine for central hypothyroidism 5.
• Target free T4 in the mid-to-upper normal range since TSH cannot guide therapy 1.
• Continue monitoring for other pituitary hormone deficiencies monthly for 6 months, then every 3 months for 6 months, then every 6 months for 1 year 1.
• Ensure patients with adrenal insufficiency carry medical alert identification 1.