Clinical application of free thyroxine determinations

The clinical diagnosis and management of thyroid hormone excess and deficiency are dependent on accurate laboratory measurements and the interpretation of serum free T4 and TSH values. A variety of free T4 methods are available that perform well in otherwise healthy patients with hypothyroidism or hyperthyroidism and in euthyroid subjects with mild alterations of T4 binding to serum-carrier proteins. In contrast, only free T4 values by direct equilibrium dialysis, a method that is available in larger clinical laboratories, and ultrafiltration of undiluted sera, which is a research method, provide appropriate free T4 values in the majority of patients with significant alterations of serum T4 binding, including severe nonthyroidal illnesses. In patients with a normal pituitary-thyroid hormone axis, an inverse log10-linear relationship exists between serum TSH and free T4 levels; a decreased direct equilibrium dialysis free T4 value with an elevated TSH level confirms the diagnosis of primary hypothyroidism, and an increased free T4 value with a TSH level less than 0.01 mU/L is consistent with nonpituitary hyperthyroidism. When this relationship is altered, as in nonthyroidal illnesses, TSH secreting tumors and thyroid hormone resistant states, a direct equilibrium dialysis free T4 level plus a third-generation TSH assay is the most sensitive and specific approach to diagnose thyroid hormone excess or deficiency. Use of other free T4 methods in patients with significant alterations of serum T4 binding results in a variably increased frequency of false-positive values, which require additional testing to define the thyroid hormone status.