Narrow individual variations in serum T4 and T3 in normal subjects

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 T4, T3, free T4 index, and TSH. All individuals had different variations of thyroid function tests around individual mean values (set points).

Narrow Individual Variations in Serum T4 and T3 in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease
Stig Andersen, Klaus Michael Pedersen, Niels Henrik Bruun and Peter Laurberg

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: T4 = 0.58; T3 = 0.54; free T4 index = 0.59; TSH = 0.49.

The distribution of 12 monthly measurements of total T4 in 15 healthy men (□) and in one individual, number 11 (▪). The distribution in one individual is about half the width of the distribution in the group.

One test result described the individual set point with a precision of plus or minus 25% for T4, T3, free T4 index, and plus or minus 50% for TSH. The differences required to be 95% confident of significant changes in repeated testing were (average, range): T4 = 28, 11–62 nmol/liter; T3 = 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.

A test result within laboratory reference limits is not necessarily normal for an individual

Serum TSH, total T3, total T4, and FTI in 16 normal subjects taken monthly for 12 months. Each dot represents a monthly measurement and horizontal bars indicate individual parametric means. Participants are sorted by increasing mean. Laboratory reference ranges are: TSH, 0.3–5.0; T3, 1.2–2.7; T4, 60–140; and FTI, 70–140. Large differences were seen between individual set points, and unpredictable differences were seen in variations within individuals for all thyroid function tests.

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 T4 and T3, abnormal serum TSH may indicate that serum T4 and T3 are not normal for an individual.

A condition with abnormal serum TSH but with serum T4 and T3 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 T4 and/or T3) 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 T4 and T3 within the laboratory reference range.

In conclusion

In conclusion, we found that individual reference ranges for serum T3 and T4 are about half the width of population-based reference ranges. Hence, a test result within the laboratory reference limits is not necessarily normal for the individual. Serum TSH outside the population-based reference range indicates that serum T3 and serum T4 are not normal for the individual.