Clinical Parameters Are More Likely to Be Associated with Thyroid Hormone Levels than with Thyrotropin Levels: A Systematic Review and Meta-Analysis

Abstract

Background: Though 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 thyrotropin (TSH). We, therefore, addressed the question as to whether levels of thyroid hormones [free thyroxine (fT4), total triiodothyronine (TT3)/free triiodothyronine (fT3)], or TSH levels, within and beyond the reference ranges, provide the better guide to the range of clinical parameters associated with thyroid status. Methods: A PubMed/MEDLINE search of studies up to October 2019, examining associations of levels of thyroid hormones and TSH, taken simultaneously in the same individuals, with clinical parameters was performed. We analyzed atrial fibrillation, other cardiac parameters, osteoporosis and fracture, cancer, dementia, frailty, mortality, features of the metabolic syndrome, and pregnancy outcomes. Studies were assessed for quality by using a modified Newcastle-Ottawa score. Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. A meta-analysis of the associations was performed to determine the relative likelihood of fT4, TT3/fT3, and TSH levels that are associated with the clinical parameters. Results: We identified 58 suitable articles and a total of 1880 associations. In general, clinical parameters were associated with thyroid hormone levels significantly more often than with TSH levels-the converse was not true for any of the clinical parameters. In the 1880 considered associations, fT4 levels were significantly associated with clinical parameters in 50% of analyses. The respective frequencies for TT3/fT3 and TSH levels were 53% and 23% (p < 0.0001 for both fT4 and TT3/fT3 vs. TSH). The fT4 and TT3/fT3 levels were comparably associated with clinical parameters (p = 0.71). More sophisticated statistical analyses, however, indicated that the associations with TT3/fT3 were not as robust as the associations with fT4. Conclusions: Thyroid hormones levels, and in particular fT4 levels, seem to have stronger associations with clinical parameters than do TSH levels. Associations of clinical parameters with TSH levels can be explained by the strong negative population correlation between thyroid hormones and TSH. Clinical and research components of thyroidology currently based on the measurement of the thyroid state by reference to TSH levels warrant reconsideration.

<p>Low Yield of Thyroid-Function Tests in Adult Hospitalized Patients — A Retrospective Analysis</p>

“…Interestingly, in their recent meta-analysis of 58 studies, Fitzgerald et al demonstrated thyroid-hormone levels (FT 4 , TT 3 /FT 3 ) had a stronger correlation with clinical parameters than TSH levels, and recommended reconsidering the current practice of a TSH-based approach to defining thyroid function. 23 Our study has a few limitations: its retrospective design; the fact that it was a single-center study conducted at an academic center; the predominantly Caucasian study population; inpatient services, such as pediatrics, obstetrics-gynecology, and surgery, were not included; we did not research clinical features linked to the ordering of TFTs; and lastly we did not analyze providers' reasoning behind the ordering of the thyroid assays and arrival at a diagnosis. However, our study adds to the growing literature demonstrating low yield of thyroid labs in the inpatient setting.…”

Associations of Thyroid Hormones and Resting Heart Rate in Patients Referred to Coronary Angiography

“…The general finding that free thyroid hormones are largely associated with RHR whereas TSH is not, is not surprising as TSH is not a perfect mirror of thyroid hormone status, whereas FT3 and FT4 are the hormones of interest that may also exert some rapid effects that can either be thyroid hormone receptor dependent or independent [18,19]. A meta-analysis has also confirmed that thyroid hormones are better correlated to various clinical parameters than TSH concentrations [20]. In line with this, a systematic review and individual participant meta-analysis in euthyroid individuals documented that FT4 but not TSH is associated with increased risk of incident atrial fibrillation [21].…”

The Two Faces of Janus: Why Thyrotropin as a Cardiovascular Risk Factor May Be an Ambiguous Target

“…Hence, a dual etiology may explain the findings of previous studies. To resolve this ambiguity, measurements of peripheral thyroid hormones are required (11) and should be integrated into future studies-not only for the selection of subjects but also for functional assessment (10,57,58). Calculated parameters providing biomarkers for the set point of thyroid homeostasis and peripheral hormone metabolism may provide additional insights, especially in the setting of clinical trials (41).…”

“…At least in elderly subjects, the benefits of levothyroxine substitution are questionable (5). While increased and high-normal free thyroxine (FT4) concentration is a well-established risk factor for malignant arrhythmia and sudden cardiac death (6,7), the association between thyrotropin (TSH) concentration and cardiovascular mortality is less well understood (8)(9)(10)(11). Studies reported either no relation at all (12,13) or a rather complex Ushaped association (14,15), as has been shown in a recent population study based on the large NHANES datasets (16).…”