Empirical Thyrotropin-Free Thyroxine Relationship Across the Thyrotropin Spectrum and Implications for Reference Intervals
Authors' conclusion
The TSH-FT4 relationship over the entire functional TSH range is segmented rather than uniformly log-linear, and the interval over which FT4 changes little may represent physiological homeostasis. Population-based TSH reference intervals showed partial concordance with the empirically derived homeostatic range, particularly at the upper end, whereas the lower boundary was less closely aligned.
Study context
- Population
- Untreated outpatients (median age 43 years, IQR 33–54) with paired TSH-FT4 measurements, July 2021–March 2024; TSH receptor antibody–positive patients and measurements during LT4, liothyronine or antithyroid drug treatment or pregnancy excludedpaired TSH-FT4 measurements
- Participants
- 782 outpatients
- Outcome
- Optimal TSH breakpoints in the relationship of FT4 to log-transformed TSH, compared with current TSH reference limits
Methodological detailssegmented regression, July 2021–March 2024
- Segmented regression
- July 2021–March 2024
Main finding
As reported in the abstract
TSH breakpoints in the TSH-FT4 relationship
- Best-fitting model by Akaike Information Criterion
- two-breakpoint model
- Lower TSH breakpoint
- 0.22 mIU/L
- Upper TSH breakpoint
- 4.25 mIU/L
- Lower breakpoint closely matched assay-specific lower reference limit but lay below harmonized lower limits in Japan and the US
- 0.27 mIU/L
- Upper breakpoint close to assay-specific upper limit
- 4.20 mIU/L
- Upper breakpoint close to harmonized upper limits (Japan and US, respectively)
- 4.23 and 4.27 mIU/L
Observational data: associations, not effects.
Original publication
Empirical Thyrotropin-Free Thyroxine Relationship Across the Thyrotropin Spectrum and Implications for Reference Intervals. Thyroid. Published 21 April 2026. doi:10.
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