Background <p>To identify determinants of unbound bilirubin (UB) and assess whether the total bilirubin/albumin ratio (TB/Alb) can serve as a surrogate index in neonates.</p> Methods <p>We retrospectively analyzed 2248 serum samples from 741 infants in a single neonatal intensive care unit (January 2022–October 2025). UB, total bilirubin (TB), direct bilirubin (DB), and albumin (Alb) were measured. Linear mixed-effects models with infant as a random effect accounted for repeated measurements and assessed determinants of UB and its association with TB/Alb. A mixed-effects logistic model evaluated the prediction of UB ≥ 0.6 µg/dL. Receiver operating characteristic analysis assessed the identification of UB ≥ 0.8 µg/dL using TB/Alb.</p> Results <p>UB increased with TB and DB and decreased with Alb. TB/Alb was strongly associated with UB and predicted UB ≥ 0.6 µg/dL. For UB ≥ 0.8 µg/dL, the optimal TB/Alb cutoff was 4.0 (sensitivity 0.94, specificity 0.85; area under the curve 0.95).</p> Conclusion <p>In routine clinical samples, UB was primarily determined by TB and Alb concentrations. TB/Alb showed a clear dose–response relationship with UB and accurately identified high UB, supporting its use when direct UB measurement is unavailable.</p> Impact <p><UnorderedList Mark="Bullet"> <ItemContent> <p>Unbound bilirubin (UB), the biologically relevant fraction associated with neurotoxicity, is difficult to measure routinely in many neonatal units.</p> </ItemContent> <ItemContent> <p>In 2248 clinical samples from 741 infants, the total bilirubin/albumin ratio (TB/Alb) showed a strong linear association with UB (UB = 0.165 × TB/Alb − 0.116).</p> </ItemContent> <ItemContent> <p>TB/Alb = 4 identified high UB levels (≥0.8 µg/dL) with excellent discrimination (AUC 0.952; optimal cutoff 4.03).</p> </ItemContent> <ItemContent> <p>TB/Alb can serve as a practical surrogate for UB, enabling rapid bedside risk stratification where UB testing is unavailable.</p> </ItemContent> </UnorderedList></p>

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Determinants of unbound bilirubin and clinical utility of the total bilirubin/albumin ratio in neonates

  • Hiroshi Miyabayashi,
  • Yuri Kubota,
  • Koichiro Hara,
  • Katsuya Saito,
  • Nobuhiko Nagano,
  • Ichiro Morioka

摘要

Background

To identify determinants of unbound bilirubin (UB) and assess whether the total bilirubin/albumin ratio (TB/Alb) can serve as a surrogate index in neonates.

Methods

We retrospectively analyzed 2248 serum samples from 741 infants in a single neonatal intensive care unit (January 2022–October 2025). UB, total bilirubin (TB), direct bilirubin (DB), and albumin (Alb) were measured. Linear mixed-effects models with infant as a random effect accounted for repeated measurements and assessed determinants of UB and its association with TB/Alb. A mixed-effects logistic model evaluated the prediction of UB ≥ 0.6 µg/dL. Receiver operating characteristic analysis assessed the identification of UB ≥ 0.8 µg/dL using TB/Alb.

Results

UB increased with TB and DB and decreased with Alb. TB/Alb was strongly associated with UB and predicted UB ≥ 0.6 µg/dL. For UB ≥ 0.8 µg/dL, the optimal TB/Alb cutoff was 4.0 (sensitivity 0.94, specificity 0.85; area under the curve 0.95).

Conclusion

In routine clinical samples, UB was primarily determined by TB and Alb concentrations. TB/Alb showed a clear dose–response relationship with UB and accurately identified high UB, supporting its use when direct UB measurement is unavailable.

Impact

Unbound bilirubin (UB), the biologically relevant fraction associated with neurotoxicity, is difficult to measure routinely in many neonatal units.

In 2248 clinical samples from 741 infants, the total bilirubin/albumin ratio (TB/Alb) showed a strong linear association with UB (UB = 0.165 × TB/Alb − 0.116).

TB/Alb = 4 identified high UB levels (≥0.8 µg/dL) with excellent discrimination (AUC 0.952; optimal cutoff 4.03).

TB/Alb can serve as a practical surrogate for UB, enabling rapid bedside risk stratification where UB testing is unavailable.