Evaluating and Managing Suspected Central Hypothyroidism on Levothyroxine
Immediate Diagnostic Confirmation
When you encounter low TSH with low free T4 in a patient on levothyroxine, immediately suspect central hypothyroidism and conduct comprehensive pituitary function testing before any dose adjustments. 1
The diagnostic workup must include:
- Morning (8 AM) cortisol and ACTH levels to assess for central adrenal insufficiency, which occurs in >75% of patients with hypophysitis 1
- Free T4 levels (not just TSH) since TSH is unreliable in central hypothyroidism—maintain free T4 in the upper half of normal range 2, 3
- Gonadal hormones: testosterone in men, estradiol in women, plus FSH and LH 1
- MRI of the sella with pituitary cuts to evaluate for pituitary enlargement, stalk thickening, or suprasellar convexity 1
Critical Safety Protocol: Rule Out Adrenal Insufficiency First
Never increase levothyroxine before confirming adequate cortisol levels—this can precipitate life-threatening adrenal crisis. 1, 4, 5, 3, 6
In patients with both central hypothyroidism and adrenal insufficiency:
- Start physiologic dose corticosteroids at least 1 week before initiating or increasing thyroid hormone 1, 4
- The increased cortisol metabolism from thyroid hormone can trigger adrenal crisis if cortisol is low 4
- This applies to all suspected central hypothyroidism cases, not just confirmed hypophysitis 1
Distinguishing Central from Primary Hypothyroidism
Central hypothyroidism presents with:
- Low or inappropriately normal TSH alongside low free T4 7
- TSH may be normal, low, or even slightly elevated (but inappropriately so given the low T4) 6, 7
- Often accompanied by other pituitary hormone deficiencies (>50% have panhypopituitarism) 1
- Headache (85%) and fatigue (66%) are common presenting symptoms 1
The key diagnostic criterion: ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, OR ≥2 pituitary hormone deficiencies with headache and symptoms. 1
Levothyroxine Management in Central Hypothyroidism
Once adrenal insufficiency is addressed:
- Monitor free T4 levels, not TSH, for dose titration 2, 3
- Target free T4 in the upper half of the normal range 2, 3, 7
- Start with physiologic replacement doses of levothyroxine (typically 1.6 mcg/kg/day in younger patients without cardiac disease) 4
- For elderly or cardiac patients, start at 25-50 mcg/day and titrate slowly 4, 8
Monitoring Protocol
- Check free T4 (not TSH) every 6-8 weeks during dose titration 2
- TSH remains unreliable for monitoring in central hypothyroidism 2, 7
- Once stable, monitor free T4 every 6-12 months 2
- Continue monitoring other pituitary hormones as central hypothyroidism rarely occurs in isolation 1
Common Pitfalls to Avoid
- Never rely on TSH alone when central hypothyroidism is suspected—always measure free T4 simultaneously 5, 7
- Do not assume hypothyroidism is primary based on symptoms alone—central hypothyroidism lacks specific clinical signs that distinguish it from primary hypothyroidism 7
- Never start thyroid hormone before ruling out adrenal insufficiency in suspected pituitary disease—this is the most dangerous error 1, 4, 5
- Avoid using TSH targets from primary hypothyroidism guidelines—these do not apply to central hypothyroidism 2, 3
Special Considerations for Immune Checkpoint Inhibitor-Induced Hypophysitis
If the patient is on immunotherapy:
- Hypophysitis occurs in ≤10% with ipilimumab monotherapy and ≤13% with combination ipilimumab/nivolumab 1
- Median time to diagnosis is 8-9 weeks after starting ipilimumab 1
- Continue immune checkpoint inhibitor therapy in most cases—high-dose corticosteroids are rarely required for thyroid dysfunction alone 4
- Monitor TSH and free T4 before each cycle initially, then every 3 months 1
- Central hypothyroidism from hypophysitis is usually permanent and requires lifelong replacement 1