Evaluate for Central (Secondary) Hypothyroidism and Rule Out Adrenal Insufficiency Before Treatment
The combination of normal TSH with low T4 and low Free Thyroxine Index (FTI) strongly suggests central hypothyroidism due to pituitary or hypothalamic dysfunction, not primary thyroid disease. This pattern requires a fundamentally different diagnostic and therapeutic approach than primary hypothyroidism 1.
Critical First Step: Rule Out Adrenal Insufficiency
Before initiating any levothyroxine therapy, you must exclude concurrent adrenal insufficiency, as starting thyroid hormone replacement without adequate cortisol can precipitate life-threatening adrenal crisis 2, 3. This is particularly critical in central hypothyroidism where multiple pituitary hormone deficiencies often coexist 1.
Immediate Diagnostic Workup
- Measure morning cortisol (8 AM) and ACTH levels to assess adrenal function 2
- Perform short cosyntropin stimulation test (250 µg) if morning cortisol is equivocal, with peak cortisol <500 nmol/L diagnostic of adrenal insufficiency 2
- Evaluate for other pituitary hormone deficiencies (prolactin, LH, FSH, GH, IGF-1) as central hypothyroidism rarely occurs in isolation 1
- Obtain pituitary MRI to identify structural lesions (adenoma, empty sella, infiltrative disease, prior surgery/radiation) 1
Understanding the Laboratory Pattern
In central hypothyroidism, TSH cannot be used as a reliable screening or monitoring test because the pituitary fails to produce adequate TSH despite low thyroid hormone levels 3, 1, 4. The TSH may be low, normal, or even slightly elevated, but it is always inappropriately low relative to the degree of hypothyroidism 1, 4.
- The low FT4 and low FTI confirm true tissue hypothyroidism despite the "normal" TSH 1
- The FTI may be particularly helpful in detecting central hypothyroidism when FT4 is in the low-normal range 1
- This pattern distinguishes central hypothyroidism from primary hypothyroidism (where TSH would be markedly elevated) and from euthyroid sick syndrome 1, 4
Treatment Protocol for Central Hypothyroidism
If Adrenal Insufficiency is Present
Initiate corticosteroid replacement at least 1 week before starting levothyroxine 2, 3. Typical physiologic replacement is hydrocortisone 15-25 mg daily in divided doses (two-thirds in morning, one-third in afternoon) 2.
Levothyroxine Initiation
- For patients <70 years without cardiac disease: Start levothyroxine 1.6 mcg/kg/day as full replacement dose 2
- For patients >70 years or with cardiac disease: Start with 25-50 mcg/day and titrate gradually 2
- Do not use TSH to guide therapy—it will remain inappropriately normal or low 3, 4
Monitoring Central Hypothyroidism
Monitor free T4 and free T3 levels, not TSH, to assess adequacy of replacement 3, 4. Target free T4 in the upper half of the reference range (ideally 16-19 pmol/L based on distribution in adequately treated primary hypothyroidism patients) 5.
- Recheck free T4 and free T3 in 6-8 weeks after dose adjustment 2
- Patients with central hypothyroidism are at high risk of under-replacement—38.9% have free T4 ≤13 pmol/l compared to only 9.5-13.4% of adequately treated primary hypothyroidism patients 5
- Once stable, monitor free T4 and free T3 every 6-12 months or with symptom changes 2
Clinical Assessment is Essential
Because TSH cannot guide therapy, clinical symptoms and signs become critical for assessing adequacy of replacement 3, 6. Monitor for:
- Resolution of fatigue, cold intolerance, weight gain, constipation, cognitive slowing 3, 6
- Normalization of heart rate, blood pressure, and reflexes 6
- Improvement in quality of life measures 6
Common Pitfalls to Avoid
- Never start levothyroxine before ruling out adrenal insufficiency in suspected central hypothyroidism—this can precipitate adrenal crisis 2, 3
- Never rely on TSH to diagnose or monitor central hypothyroidism—it is unreliable and will lead to under-treatment 3, 1, 4
- Avoid assuming all hypothyroidism is primary—failure to recognize central hypothyroidism leads to missed pituitary pathology and inadequate treatment 1, 4
- Do not accept low-normal free T4 levels as adequate replacement—target the upper half of the reference range 5
- Failing to evaluate for other pituitary hormone deficiencies when central hypothyroidism is diagnosed 1
Why This Pattern Differs from Primary Hypothyroidism
In primary hypothyroidism, the thyroid gland fails and TSH rises appropriately 3. In central hypothyroidism, the pituitary or hypothalamus fails to produce adequate TSH, so the thyroid gland receives insufficient stimulation despite being structurally normal 3, 1. This fundamental difference explains why: