Calculated Serum Antioxidant Capacity Masks Opposite Associations of Urate and Unconjugated Bilirubin with Leukocyte Count: A Ten-Year Cross-Sectional Hospital Laboratory Study Including 25-Hydroxyvitamin D

Calculated total antioxidant capacity (cTAC), a weighted sum of albumin, urate and bilirubin, is often interpreted as a single antioxidant dimension. We asked whether its constituents share the same association with leukocyte count, a routine but nonspecific marker of the inflammatory, oxidant-generating cell compartment, and examined 25-hydroxyvitamin D [25(OH)D]. In this retrospective cross-sectional study of routine records from a tertiary university hospital laboratory (2014–2023; 20,525 patient-years, 14,152 adults), cTAC was calculated with Trolox-equivalent coefficients (0.63·albumin + 1.02·urate + 1.50·bilirubin). Patient-clustered models of log leukocyte count, leukopenia (<4 × 109/L) and leukocytosis (≥10 × 109/L) were adjusted for age, sex, season and era, and additionally for estimated glomerular filtration rate and alanine aminotransferase. Urate accounted for 90% of the variance of cTAC. cTAC showed a U-shaped association with leukocytosis, whereas its components diverged. Per standard deviation, urate was associated with more leukocytes (+4.2%, 95% CI 3.2–5.2; leukocytosis odds ratio [OR] 1.23, 1.14–1.32) and calculated unconjugated bilirubin with fewer (−4.3%, −5.7 to −2.9; OR 0.71, 0.63–0.82). Both associations were similar after multiple imputation of missing covariates. Platelet adjustment attenuated the bilirubin estimate to −1.4%, whereas haemoglobin adjustment did not; with platelet counts of 150–400 × 109/L and no anaemia, it was −3.8% (−5.0 to −2.7). 25(OH)D was weakly inversely associated (−1.2%, −1.8 to −0.6), without evidence of effect modification. In this cross-sectional setting, in which residual confounding is likely, a single calculated antioxidant capacity statistically conceals opposite-signed associations of its constituents with leukocyte count.