Narrow Individual Variations in Serum T₄and T₃in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease

Abstract

High individuality causes laboratory reference ranges to be insensitive to changes in test results that are significant for the individual. We undertook a longitudinal study of variation in thyroid function tests in 16 healthy men with monthly sampling for 12 months using standard procedures. We measured serum T(4), T(3), free T(4) index, and TSH. All individuals had different variations of thyroid function tests (P < 0.001 for all variables) around individual mean values (set points) (P < 0.001 for all variables). The width of the individual 95% confidence intervals were approximately half that of the group for all variables. Accordingly, the index of individuality was low: T(4) = 0.58; T(3) = 0.54; free T(4) index = 0.59; TSH = 0.49. One test result described the individual set point with a precision of +/- 25% for T(4), T(3), free T(4) index, and +/- 50% for TSH. The differences required to be 95% confident of significant changes in repeated testing were (average, range): T(4) = 28, 11-62 nmol/liter; T(3) = 0.55, 0.3--0.9 nmol/liter; free T4 index = 33, 15-61 nmol/liter; TSH = 0.75, 0.2-1.6 mU/liter. Our data indicate that each individual had a unique thyroid function. The individual reference ranges for test results were narrow, compared with group reference ranges used to develop laboratory reference ranges. Accordingly, a test result within laboratory reference limits is not necessarily normal for an individual. Because serum TSH responds with logarithmically amplified variation to minor changes in serum T(4) and T(3), abnormal serum TSH may indicate that serum T(4) and T(3) are not normal for an individual. A condition with abnormal serum TSH but with serum T(4) and T(3) within laboratory reference ranges is labeled subclinical thyroid disease. Our data indicate that the distinction between subclinical and overt thyroid disease (abnormal serum TSH and abnormal T(4) and/or T(3)) is somewhat arbitrary. For the same degree of thyroid function abnormality, the diagnosis depends to a considerable extent on the position of the patient's normal set point for T(4) and T(3) within the laboratory reference range.

Thyroid Function and the Risk of Atherosclerotic Cardiovascular Morbidity and Mortality

“…However, euthyroid participants are known to have a small intraindividual variation of thyroid function. 36 In contrast, participants with thyroid dysfunction are prone to treatment during follow-up, which could eventually reduce their risk for atherosclerotic morbidity and mortality over time. This can explain the increased atherosclerotic risk after we excluded the users of thyroid function-altering medications from the analyses.…”

“…38 In addition, our results were consistent within the normal range of thyroid function, which is considered to be stable with small intraindividual variability. 36 We lacked information on serum triiodothyronine levels. However, TSH and FT4 represent the most relevant measurements of thyroid function in clinical practice.…”

2013 ETA Guideline: Management of Subclinical Hypothyroidism

“…In addition, measurement of serum FT 4 is necessary to rule out overt hypothyroidism. Although the reference range for serum TSH in the general adult population is between 0.4 and 4.0 mU/l, TSH concentrations in a healthy individual have a much smaller variation over time, approximating to a third of the reference interval [14]. This can be conceptualised as an individual's ‘TSH setpoint'.…”

Is the TSHR D727E polymorphism a genetic predisposition for multinodular goiter in the Turkish population?

“…Genetic factors account for about 65% of the variation in serum TSH, fT4, and fT3 levels (Andersen et al, 2002;Hansen et al, 2004). Therefore, the polymorphism we studied might also be associated with a decreased level of TSH in healthy controls.…”