Composite reference interval for thyroid-stimulating hormone and free thyroxine, comparison with common cutoff values, and reconsideration of subclinical thyroid disease

BACKGROUND: Examination of the 2-dimensional probability distribution of thyroid-stimulating hormone (TSH) and free thyroxine (FT₄) shows that the widths of the TSH and FT₄ reference intervals derived from this bivariate distribution are mutually interdependent, an aspect commonly ignored when interpreting thyroid testing results with separate reference intervals for TSH and FT₄. We desired to establish and critically evaluate a composite reference interval for TSH and FT₄ to allow bivariate classification of biochemical thyroid conditions. METHODS: FT₄ and TSH results of 871 healthy individuals [361 women and 510 men, 18-40 years old, without history of thyroid-related disease or medication, negative for anti-thyroid peroxidase (anti-TPO) antibody] were transformed to standard normal variables by logarithmic transformation with correction for skewness and subsequent normalization. We established a 95% reference interval of the distance of each FT₄/TSH pair of values to the center of the 2-dimensional probability distribution. RESULTS: The bivariate 95% reference interval is enclosed by a circular profile with radius 2.45 SD. By contrast, conventional reference intervals comprise a square with the boundaries of -1.96 and +1.96 SD for both FT₄ and TSH that enclose only 90% of all data. Compared with the ±1.96 SD square, the bivariate reference interval classified 4% fewer of 3651 healthy individuals older than 40 years as subclinically hyperthyroid and 14% fewer of 712 anti-TPO-positive healthy individuals as subclinically hypothyroid. CONCLUSIONS: Conventional application of separate cutoff values for FT₄ and TSH leads to overestimation of the incidence of subclinical thyroid disease. Application of a composite overall reference interval is recommended.