BACKGROUND
The normal range of thyroid function tests is determined by measuring Free T4 and TSH levels in a population of healthy adults with no thyroid problems. Those results in the middle 95% are considered the normal range; the 2.5% above these levels and the 2.5% below these levels are considered abnormal. The diagnosis of hyperthyroidism is made with the Free T4 levels is in the 2.5% above the normal range and the TSH is in the 2.5% below the normal range. Conversely, the diagnosis of hypothyroidism is made with the Free T4 levels is in the 2.5% below the normal range and the TSH is in the 2.5% above the normal range.

Determining the normal ranges this way does not take into consideration the risk of non-thyroid disease associated with thyroid hormone levels. There has long been known about an association between thyroid levels and heart disease and death. For example, in 2015, Dr. Cappola’s group from University of Pennsylvania found that higher free T4 values even with the “normal” range might increase the risk of death in elderly patients. By contrast, a 2014 international study conducted at Johns Hopkins showed that free T4 levels on the lower end of the normal range might also increase risk of death in younger patients (average age 40).

This study was done to see if the normal range of thyroid function tests needs to be adjusted to better reflect patients’ risk of heart disease and death.

THE FULL ARTICLE TITLE
Xu Y et al Thyroid Studies Collaboration 2023 The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: Systematic review and individual participant data meta-analysis. Lancet Diabetes Endocrinol 11:743–754. PMID: 37696273.

SUMMARY OF THE STUDY
Studies from the Thyroid Studies Collaboration (1950-2020) and various online databases (2010-2017) were evaluated to determine TSH and Free T4 hormone levels and risk of death and heart disease on patients older than 18. Pregnant patients and patients with known thyroid or cardiac disease were not included in the analysis. A total of 134,346 participants were followed for an average of 11.5 years. Half of the participants were female, and their average age was 59. Only 4.3% of the group were on thyroid medication. The normal range of Free T4 and TSH were divided into 10 equal groups (percentiles) for analysis.

Individuals with free T4 levels within the 20th to 40th percentile for normal free T4 value ranges had the least risk of death and heart disease. When the 80th to 100th percentile group for the normal free T4 value range was compared to this 20th to 40th percentile group, their risk of heart disease-related death was 57% higher, any type of death was 34% higher, heart disease was 22% higher, and both heart disease and any type of death was 20% higher. For female patients above the age of 70 who had a free T4 value above the 85th percentile of the normal range, their absolute risk of death and having heart disease was greater than 5%. For male patients above the age of 70 who had a free T4 value above the 75th percentile of the normal range, their absolute risk of death and having heart disease was greater than 5%.

Participants who fell within the 60th to 80th percentile for normal TSH value ranges had the least risk of death and heart disease. When the 0 to 20th percentile group for the normal TSH value range was compared to this 60th to 80th percentile group, their risk of heart diseaserelated death was 7% higher, any type of death was 9% higher, and both heart disease and any type of death was 7% higher.

WHAT ARE THE IMPLICATIONS OF THIS STUDY?
Especially in the elderly population, higher percentiles of the free T4 reference range of lower percentiles of the TSH reference range were associated with higher rates of deaths from any reason as well as specifically cardiac reasons. The 60th to 80th percentile for normal TSH value ranges and 20th to 40th percentile for normal free T4 value ranges were determined to be the healthy ranges with the least association with death and heart disease. This study suggests that the “normal” thyroid function reference ranges might not be suitable for the elderly and men. However, it is not known whether treating individuals in the upper and lower percentiles of the “normal” reference range would affect the disks of heart disease and/or death. However, this study raises the possibility that clinicians should consider changing the “normal” Free T4 and TSH reference ranges for patients as they age, to help decrease the risk of heart disease.

— Pinar Smith, MD

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