When assessing thyroid function, thyroid hormone levels ― particularly free thyroxine (FT4) levels ― consistently show stronger associations with a wide array of clinical conditions than the standard measure of thyroid stimulating hormone (TSH), according to a systematic review and meta-analysis of more than 50 studies.
The new findings suggest the need for a rethink of the long-held paradigm of primarily measuring TSH when assessing thyroid status, including in clinical practice guidelines, the authors assert in their article in Thyroid.
Lead author Stephen P. Fitzgerald, MBBS, FRACP, of the Royal Adelaide Hospital, Australia, told Medscape Medical News that, on the basis of their previous work on thyroid physiology, “We would have been surprised to find TSH to be more associated with clinical parameters than FT4…even though current practice bases thyroid assessment on TSH levels.”
But, “We did not expect our findings to be so convincing,” he noted.
“We found no indication of, or reference to, any work that suggested that TSH levels consistently indicate thyroid status of any organ or tissue more strongly than thyroid hormone levels,” he and his colleagues say.
“We suspected that current practice could be improved,” Fitzgerald told Medscape Medical News. “Reconsideration of the TSH-based diagnostic approach to thyroid function appears to be indicated.”
One caveat of the analysis is that a plethora of additional factors is associated with the clinical conditions that were observed, noted Angela M. Leung, MD, associate professor of medicine in the Division of Endocrinology, Diabetes, and Nutrition at the University of California, Los Angeles, David Geffen School of Medicine, in commenting on the study for Medscape Medical News.
“It is important to note that the etiologies of these various clinical conditions, including atrial fibrillation, osteoporosis, fractures, and frailty, are multifactorial, and thyroid status is but one of many parameters impacting these conditions,” she explained.
“That being said, it is interesting that serum free T4 levels were associated with these and other health conditions in about 50% of the analyses in this study, in contrast to serum TSH that was not as strongly associated,” she noted.
But another expert, Maria Papaleontiou, MD, an assistant professor with the Division of Metabolism, Endocrinology and Diabetes, University of Michigan, Ann Arbor, expressed apprehension over the suggestion of changes in guidelines.
“I think that more research is needed to better understand how active thyroid hormone levels correlate with adverse clinical outcomes before reconsidering the status quo,” she told Medscape Medical News.
“A test result is only as good as the test, and despite pitfalls, TSH assays have the least variation in assay performance and thus are considered more accurate,” she added.
“Additionally, TSH is exquisitely sensitive to subtle thyroid hormone changes,” she noted.
Assessment of Thyroid Function on the Basis of Level of Controlling Hormone TSH
In their article, Fitzgerald and colleagues explain that, although the functional states of other endocrine systems are not defined on the basis of levels of controlling hormones, the assessment of thyroid function is based on levels of the controlling hormone TSH.
So in their meta-analysis, they addressed the question as to whether levels of thyroid hormones (FT4, total triiodothyronine/free triiodothyronine [TT3/FT3]) or TSH levels, within and beyond the reference ranges, provide the better guide to the range of clinical parameters associated with thyroid status.
They identified 58 articles published through October 2019 that describe FT4, TSH, TT3/FT3, and the associations of their reference ranges with clinical parameters, including atrial fibrillation and other cardiac parameters, osteoporosis, fracture, cancer, dementia, mortality, pregnancy outcomes, and others.
The studies included a total of 1880 associations; among them, FT4 levels were significantly associated with clinical conditions in 50% of analyses.
TT3/FT3 and TSH levels were associated with the parameters in 53% and 23% of the analyses, respectively.
Although the associations with FT4 and TT3/FT3 and the parameters were similar (P = .71), both were significantly greater than with TSH (P < .0001 for each vs TSH).
A more sophisticated statistical analysis showed that TT3/FT3 were not as robust in their link to clinical parameters as FT4, the authors note.
Despite the prominent role of TSH in the assessment of thyroid status, not one of the studies showed TSH to be a stronger indicator in clinical parameters than either FT4 or TT3/FT3.
“In our sample we found no indication of, or reference to, any work that suggested that TSH levels consistently indicate thyroid status of any organ or tissue more strongly than thyroid hormone levels,” say Fitzgerald and colleagues.
TSH Linear Link to T4, T3; but Is It Time to Challenge Dogma?
Leung noted, however, that TSH has long been the standard measure for thyroid assessment because it has been regarded as a reliable indicator of thyroid hormone levels.
“The reason why TSH is recommended as the initial screen of potential thyroid dysfunction is the log-linear relationship that exists between TSH and the peripheral thyroid (T4 and T3) hormone levels,” she explained.
“Since small changes in T4 and T3 would be reflected by much larger, exponential changes in TSH, the TSH is thought to be a more accurate marker and earlier signal of potential thyroid status abnormalities.
“Given this, the associations found for FT4 would be usually expected to be true for TSH as well,” she said.
But Fitzgerald told Medscape Medical News that even if their results only showed FT4 to be equal to TSH, rather than superior, “that would have challenged the current dogma to a degree.
“Our findings enable a clearer distinction still,” he asserted.
Role of TSH in Monitoring Thyroid Treatments Debated
Fitzgerald and colleagues also argue that even in the management of hyper- or hypothyroidism, their evidence suggests that “there is no apparent a priori reason why TSH levels should be preferred over thyroid hormone levels in the context of monitoring thyroid treatments.
“Though TSH levels remain good screening tests for overt thyroid dysfunction, it is theoretically and empirically more sound to rely on thyroid hormone and especially FT4 levels to classify the thyroid state,” they add.
Papaleontiou expresses reservations, however, regarding these conclusions.
“I would caution against extrapolating these results to patients on thyroid hormone therapy, as the FT4 and FT3 levels in these patients are not necessarily the same as in those without thyroid dysfunction at same TSH levels,” she said.
The authors and Leung have disclosed no relevant financial relationships.
Thyroid. Published online April 29, 2020. Abstract