Free Thyroxine (FT4) and Free Triiodothyronine (FT3) Estimate Tests

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Nomenclature of Free T4 (FT4) and Free T3 (FT3) Estimate Methods

Considerable confusion encompasses the nomenclature of free thyroid hormone tests. Controversy continues regarding the technical validity of the measurements themselves and their clinical utility in conditions associated with binding protein abnormalities.[145,147,148,150,151] Free hormone testing in clinical laboratories are made using either index methods that require two separate tests, single-test ligand assays or physical separation methods that isolate free from protein-bound hormone prior to direct measurement of hormone in the free fraction. Ligand assays are standardized either with solutions containing gravimetrically established concentrations of hormone, or use calibrators with values assigned by a physical separation method (i.e. equilibrium dialysis and/or ultrafiltration). Physical separation methods typically are manual, technically demanding and quite expensive for routine clinical use. Index and ligand assay tests are more commonly used in the clinical laboratory setting, where they are typically performed on automated immunoassay analyzer platforms.[17]

Guideline 11. Free Hormone Test Nomenclature

  • The free hormone methods used by most clinical laboratories (indexes and immunoassays) do not employ physical separation of bound from free hormone and do not measure free hormone concentrations directly! These tests are typically binding protein dependent to some extent and should more appropriately be called "Free Hormone Estimate" tests, abbreviated FT4E and FT3E.

  • In general, Free Hormone Estimate tests overestimate the FT4 level at high protein concentrations and underestimate FT4 at low protein concentrations.

Unfortunately, a confusing plethora of terms have been used to distinguish the different free hormone methods and the literature is filled with inconsistencies in the nomenclature of these tests. Currently, there is no clear methodologic distinction between terms such as "T7", "effective thyroxine ratio", "one-step", "analog", "two step", "backtitration", "sequential", "immunoextraction" or "immunosequestration", "ligand assay" because manufacturers have modified the original techniques or adapted them for automation.[147] Following the launch of the original one-step "analog" tests in the 1970s, the term "analog" became mired in confusion.[147] This first generation of hormone-analog tests were shown to be severely binding-protein dependent and have since been replaced by a new generation of labeled-antibody "analog" tests which are more resistant to the presence of abnormal binding proteins.[147,152] Unfortunately, manufacturers rarely disclose all assay constituents or the number of steps involved in an automated procedure so that it is not possible to use the method's nomenclature (two-step, analog etc) to predict its diagnostic accuracy for assessing patients with binding protein abnormalities.[152]