To assess thyroid function, clinicians typically determine blood levels of thyroid-stimulating hormone (TSH) and thyroxine (T4) and do not directly measure triiodothyronine (T3).
However, findings from a large observational study of a US sample of adults with normal thyroid function suggested that subclinical variation in the hypothalamic-pituitary-thyroid (HPT)–axis effector hormone T3 “is an important and overlooked factor linking socioeconomic forces, human biology, and aging,” researchers reported.
The study, with lead author Ralph I. Lawton, an MD-PhD student at Harvard Medical School, Boston, Massachusetts, was published online on January 4, 2024, in Proceedings of the National Academy of Sciences.
In this national sample of healthy adults older than 20, free T3 was negatively related to household income.
At age 40 and older, free T3 was significantly linked to being employed.
And among adults from age 51 to 80, free T3 levels were inversely related to mortality.
“It is important to note that the more typically measured biomarkers for thyroid function (T4 and TSH) are poorly linked to free T3 levels,” Lawton and colleagues wrote.
The ratio of TSH:T4 explained only 1.7% of variation in T3 levels, they noted, which suggested that TSH and T4 may not be accurate surrogates of free T3.
Thus, “direct measurement of free T3 is likely vital to properly stratify the effects of HPT-axis variation,” they maintained.
“Improved methods for measurement [of T3] and further investigation of the role of free T3 in clinical conditions may be high yield,” according to the researchers.
Further studies of the relationship between the action of deiodinase in converting T4 to T3 and social forces and aging could elucidate critical biology.
“New therapeutics targeting T3/T4 ratios,” they suggested, “may be more beneficial for a significant cohort of older individuals [with hypothyroidism] currently treated with levothyroxine [(LT4)].”
‘Cherry on Top’
“I think this is a really important paper,” thyroidology expert Antonio Bianco, MD, PhD, Professor of Medicine, The University of Chicago, Illinois, who was not involved with this research, told Medscape Medical News.
His research group and others “have slowly been providing evidence of the relevance of measuring T3 levels,” he continued. “This paper is sort of a cherry on top. It is really the most recent strong evidence that looking at T3 levels in plasma is really important.”
“We need to do a better job at developing a much more precise assay for T3,” he said, “because now we know T3 is a very important parameter that endocrinologists should be looking for.”
“We know that about 20 million Americans have hypothyroidism, being treated with T4 (levothyroxine),” Bianco continued.
“As endocrinologists, we believe that if you treat someone with levothyroxine, you normalize T3 levels. However, many times, with standard of care with levothyroxine, T3 levels are not normalized.”
Larger Variations in T3
Thyroid hormones (TSH, free T4, and free T3) influence many aspects of human physiology and behavior, but it is not known how variations in these levels in a population free of thyroid disease are associated with mortality and socioeconomic factors.
The researchers analyzed data from 7626 adults over age 20 up to age 80 who participated in the National Health and Nutrition Examination Survey during 2007-2012 and had blood tests to determine TSH, free T4, and free T3 and were not being actively treated for thyroid conditions.
Among the 3603 older adults (over age 50), there were 981 deaths up until the end of 2019. TSH levels were not linked to mortality, but increasing levels of free T3 and decreasing levels of free T4 were protective for mortality (hazard ratios, 0.88 and 1.26, respectively; P <.01>
There was a robust negative relationship between household income and employment and free T3 but no relationship between these factors and T4.
There was a much larger variation across age in levels of free T3 than in levels of TSH or free T4.
Free T4 and free T3 diverged at older ages, when free T4 increased and free T3 continually decreased.
Older adults with symptoms of hypothyroidism may have high free T4 levels despite low free T3, the researchers noted.
“In a nonclinical sample representative of the US population,” they summarized, “we find that free T3 is much more strongly related to all domains studied — age, sex, seasonality, household income, employment, and longevity — than the other molecules of the HPT axis.”
This work was supported by the Burroughs Wellcome Fund Career at Scientific Interface award, a Brain and Behavior Research Foundation young investigator award, the Howard Hughes Medical Institute, the National Institute of Aging, and the National Institute of General Medical Sciences. Bianco served as a consultant for AbbVie, Avion Pharmaceuticals, Synthonics, Synthion, and Thyron and recently published the book Rethinking Hypothyroidism: Why Treatment Must Change and What Patients Can Do.
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