Narrow individual variations in serum T-4 and T-3 in normal subjects: A clue to the understanding of subclinical thyroid disease

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 plus or minus 25% for T-4, T-3, free T-4 index, and plus or minus 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 T-4 index = 33,15-61 nmol/liter; TSH = 0.75,0.2-1.6 mU/Iiter. 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.