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Narrow Individual Variations in Serum T₄ and T₃ in Normal Subjects: A Clue to the Understanding of Subclinical Thyroid Disease

Department of Endocrinology (S.A., N.H.B., P.L.) and Clinical Biochemistry (K.M.P.), Aalborg Hospital, Aalborg, Denmark DK-9000

Address all correspondence and requests for reprints to: Stig Andersen, M.D., Department of Endocrinology and Medicine, Aalborg Hospital, DK-9000 Aalborg, Denmark. E-mail: . stiga{at}dadlnet.dk

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

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