BACKGROUND
The thyroid gland produces the thyroid hormones thyroxine (T4) and triiodothyronine (T3). The production of these hormones is regulated by the pituitary hormone thyroid stimulating hormone (TSH). Measuring T4, T3 and TSH levels in the blood can determine of the thyroid is overactive (hypothyroidism), underactive (hypothyroidism) or working normally. The normal ranges of T4, T3 and TSH, also known as thyroid function tests (TFTs), are generated based on the distributions of results from a healthy population without thyroid problems. Values that are measured in the lowest 2.5% and the highest 2.5% of the population are considered “abnormal” while the “normal” range is determined by the values in remaining 95% of the population. TFTs levels in the “abnormal” range usually indicates that the thyroid is not working normally and needs to be treated.

One concern about the interpretation of TFT results is that they are a “one-size-fits-all” model, meaning that the normal ranges are applied equally during all ages of life regardless of sex, and race, all factors that a known to alter TFTs. Such simplification may contribute to both overdiagnosis and underdiagnosis of thyroid diseases, particularly in subclinical cases, when the TSH is abnormal but the T4 and T3 levels are in the normal range.

This study examines 2 population-based TFT data sets with the aim of creating more individualized TFT reference ranges and determining their expected effects on the diagnosis of abnormal thyroid status.

THE FULL ARTICLE TITLE
Li Q, et al. Thyroid function reference intervals by age, sex, and race: a cross-sectional study. Ann Intern Med. Epub 2025 May 6; doi: 10.7326/ANNALS-24-01559. PMID: 40324200.

SUMMARY OF THE STUDY
This large-scale, cross-sectional study included 8308 adults from the U.S. NHANES (National Health and Nutrition Examination Survey) and 314,302 individuals from a multicenter Chinese health checkup registry. Individuals with known thyroid disease were excluded.

In this study, TSH levels increased, and T3 levels declined with increasing age, while T4 levels remained largely unchanged. Women exhibited higher T4 but lower T3 levels than men. Individuals categorized as White had higher TSH levels than Black or Hispanic people.

After applying personalized reference intervals based on age, sex and race as compared to the standard, fixed reference intervals, 48.5% of individuals initially categorized as having subclinical hypothyroidism (high TSH and normal T4 levels) and 31.2% of individuals initially categorized as having subclinical hyperthyroidism (low TSH and normal T4 levels) were reclassified as having normal thyroid function. This reclassification was particularly noted among older patients, women and White individuals. In the analysis of a separate data set from the Chinese survey, these patterns were found to be similar.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
This study suggests that standard reference ranges of TFTs may not adequately account for changes related to age, sex and race. Different population subgroups exhibited different TSH reference intervals, especially women and those of older age. In this study, the use of reference ranges personalized based on age, sex and race significantly altered disease classification and may prevent risks of overtreatment, particularly in elderly and female patients. These results suggest that patient-specific references intervals will offer an important advance in individualized thyroid care when available.

— Alan P. Farwell, MD

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