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

Abstract

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. © 2009 American Association for Clinical Chemistry.