Target Free Thyroxine (FT4) Levels in Hypothyroidism
For primary hypothyroidism, target TSH normalization (0.45-4.5 mIU/L) rather than a specific FT4 level, as FT4 will naturally fall within the reference range when TSH is optimized. 1 However, for central (secondary/tertiary) hypothyroidism, target FT4 levels in the upper half of the normal reference range since TSH cannot guide therapy. 2, 3, 4
Primary Hypothyroidism: TSH-Guided Therapy
The goal is to normalize TSH to 0.45-4.5 mIU/L, which will result in FT4 levels within the laboratory's reference range. 1 The geometric mean TSH in disease-free populations is 1.4 mIU/L, providing a physiologic target. 1
Expected FT4 Levels on Adequate Replacement
- Patients with primary hypothyroidism on levothyroxine typically achieve FT4 levels that are higher than untreated euthyroid individuals (mean 1.36 ng/dL vs 1.10 ng/dL) to normalize TSH. 4
- The median FT4 in adequately treated primary hypothyroidism is approximately 16 pmol/L (20-80th centile range: 14-19 pmol/L). 3
- FT4 levels below 13 pmol/L in patients on levothyroxine suggest under-replacement, as only 13.4% of adequately treated primary hypothyroidism patients have FT4 this low. 3
Monitoring Strategy
- Use TSH as the primary monitoring parameter, checking every 6-8 weeks during dose titration until TSH reaches 0.45-4.5 mIU/L. 5, 2
- Free T4 can help interpret ongoing abnormal TSH levels during therapy, as TSH may take longer to normalize. 5
- Once stable, monitor TSH every 6-12 months or if symptoms change. 5
Central (Secondary/Tertiary) Hypothyroidism: FT4-Guided Therapy
For central hypothyroidism, TSH is unreliable and should NOT be used to monitor therapy—instead, titrate levothyroxine to achieve FT4 levels in the upper half of the normal reference range. 2, 3, 4
Specific FT4 Targets
- Target FT4 to the middle-upper normal range (typically the upper 50% of the laboratory's reference range). 6, 4
- Patients with central hypothyroidism require mean FT4 levels of approximately 1.31-1.36 ng/dL for adequate replacement, similar to primary hypothyroidism patients. 4
- FT4 levels in the median-lower normal range (below 1.10 ng/dL) are associated with lower FT3 levels and lower body temperature in central hypothyroidism, indicating inadequate replacement. 6
Rationale for Upper-Range Targeting
- Central hypothyroidism patients are at high risk of under-replacement, with 38.9% having FT4 ≤13 pmol/L compared to only 9.5-13.4% in primary hypothyroidism. 3
- Lower FT3 levels and FT3/FT4 ratios occur in central hypothyroidism compared to primary hypothyroidism, necessitating higher FT4 targets to achieve adequate tissue thyroid hormone levels. 6
- The peak therapeutic effect may not be attained for 4-6 weeks after dose adjustment. 2
Laboratory-Specific Considerations
Always use the laboratory's established reference range for FT4, as reference ranges vary significantly between different immunoassay platforms and manufacturers. 7 FT4 should always be interpreted in conjunction with TSH levels (in primary hypothyroidism) for comprehensive assessment. 7
Common Pitfalls to Avoid
- Never target a specific FT4 level in primary hypothyroidism—TSH normalization is the goal, and FT4 will follow. 1, 2
- Avoid under-replacement in central hypothyroidism by targeting FT4 in the lower-normal range—this leads to persistent hypothyroid symptoms and low body temperature. 6, 3
- Do not use TSH to guide therapy in central hypothyroidism, as it is unreliable and will lead to inadequate treatment. 2, 3
- Approximately 25% of patients on levothyroxine are unintentionally maintained on doses sufficient to fully suppress TSH, increasing risks for atrial fibrillation, osteoporosis, and cardiac complications—regular monitoring prevents this. 5