Impacts of new sex- and age-specific TSH and FT4 reference ranges on thyroid status and metabolic disorder associations

Abstract Context Thyroid hormone levels vary by age, sex, and genetic background; yet most clinical reference ranges (RRs) do not account for these factors, potentially leading to misclassification of thyroid status and missed associations with metabolic disorders. Objective To evaluate the impact of newly established age- and sex-specific reference ranges for thyroid-stimulating hormone (TSH) and free thyroxine (FT4) on the prevalence of thyroid statuses and their associations with metabolic disorders. Methods Cross-sectional observational studies were conducted, and we enrolled over 8,000 participants who underwent thyroid status evaluation with Abbott and Siemens assay kits. We compared the prevalence of different thyroid statuses and corresponding metabolic disorders based on the new RRs with that based on the manufacturers’ RRs. Results New RRs significantly altered the prevalence of several thyroid statuses. Subclinical hypothyroidism increased in middle-aged individuals using Abbott kits but decreased in older individuals using Siemens kits. Syndrome of inappropriate secretion of TSH (SITSH, high FT4 with normal or elevated TSH) increased significantly with both kits when applying the new RRs. SITSH, defined by the new RRs, was significantly associated with increased risks of hypertension (Abbott: odds ratio [OR] 2.00; Siemens: OR 1.70) and diabetes (Abbott: OR 2.65; Siemens: OR 1.68), whereas no such associations were observed using the manufacturers’ RRs. Conclusions Age- and sex-specific RRs corrected the misclassification of thyroid status and uncovered a previously underdiagnosed group (SITSH) associated with cardiometabolic risks. These findings support the importance of new RRs for diagnostic accuracy and clinical risk stratification.