Biological Variation of Free T4 and TSH
The within-subject biological variation (CVI) for TSH is approximately 20-34%, while free T4 demonstrates much tighter within-subject variation at approximately 3.6-5.1%, making free T4 a more stable marker for monitoring individual thyroid function over time.
Within-Subject Biological Variation (CVI)
TSH Biological Variation
- TSH demonstrates substantial within-subject biological variation of approximately 19.7-34.54% in healthy individuals 1, 2
- The within-subject variation of TSH is approximately 20% in healthy people and can reach up to 30% in patients on hemodialysis 3
- A more recent study using the Cobas 602 analyzer found CVI of 19.7% for TSH in European volunteers 1
- Turkish population data showed CVI of 22.3% (95% CI: 19.3-26.3%) for TSH 4
- The 24-hour biological variation study reported CVI of 34.54% for TSH, with males showing lower variation than females 2
Free T4 Biological Variation
- Free T4 shows much tighter within-subject variation, with CVI ranging from 3.57% to 5.1% across multiple studies 1, 2, 4
- European data demonstrated CVI of 4.6% for free T4 1
- The 24-hour variation study found CVI of 3.57% for free T4 2
- Turkish population showed CVI of 5.1% (95% CI: 4.3-6.1%) for free T4 4
- Long-term studies in patients with benign thyroid disease showed free T4 variation of less than 10% over years 5
Between-Subject Biological Variation (CVG)
TSH Between-Subject Variation
- TSH demonstrates high between-subject variation (CVG) of 26.6-37.6%, reflecting the wide population-based reference ranges 1, 4
- European volunteers showed CVG of 37.6% for TSH 1
- Turkish population data revealed CVG of 26.6% (95% CI: 19.2-39.8%) for TSH 4
Free T4 Between-Subject Variation
- Free T4 shows moderate between-subject variation with CVG of 8.0-10.8% 1, 2, 4
- European data demonstrated CVG of 10.8% for free T4 1
- The 24-hour study found CVG of 8.03% for free T4 2
- Turkish population showed CVG of 8.2% (95% CI: 6.1-12.1%) for free T4 4
Clinical Implications: Reference Change Values (RCV)
TSH Reference Change Value
- The difference in TSH concentration must exceed 54.7% in healthy people to represent a true biological change rather than normal variation 1
- For patients on hemodialysis, TSH must change by 72% to be considered significant 3
- Turkish data showed RCV of -40.3% (decrease) to +67.6% (increase) for TSH 4
Free T4 Reference Change Value
- Free T4 requires only a 12.7-16.2% change to represent true biological significance 1, 4
- European data showed RCV of 16.2% for free T4 1
- Turkish population demonstrated RCV of -12.7% (decrease) to +14.5% (increase) for free T4 4
Index of Individuality (II)
Clinical Interpretation
- TSH has an index of individuality of 0.2-0.84, indicating moderate to high individuality 1, 4
- Free T4 demonstrates II of 0.2-0.61, suggesting high individuality and supporting the use of individual monitoring rather than population-based reference ranges 1, 2, 4
- All thyroid parameters except TSH show II ≤ 0.63, indicating that population-based reference ranges have limited utility for individual patient monitoring 2
Sex Differences in Biological Variation
- Males demonstrate lower within-subject variation and lower index of individuality for all thyroid hormones compared to females 2
- Concentrations of TSH, T3, T4, free T3, and free T4 are significantly different between sexes, warranting sex-stratified interpretation 2
Long-Term Stability
- Patients on stable levothyroxine therapy show the lowest coefficient of variation (<10%) for T3 and T4 over periods of 3-13 years 5
- Even in patients without medication, T3 and T4 demonstrate variation of only approximately 10% over years 5
- TSH shows wider long-term variation, particularly after radioiodine therapy (>30%), compared to T3 and T4 5