Measuring total bilirubin for clinical decision making: are we treating at the right number?

Every clinical decision to start or discontinue phototherapy ultimately depends on a single laboratory value of a total serum bilirubin (TSB) level. Yet that value is neither the biologically most relevant marker of bilirubin neurotoxicity nor necessarily measured with sufficient analytical accuracy. Although TSB remains the most widely used clinically available marker to guide phototherapy, it is an indirect measure of bilirubin neurotoxicity. Unbound bilirubin (UB) levels are considered biologically more relevant, representing the fraction of bilirubin that can cross the blood-brain barrier and potentially cause neurotoxicity. However, UB measurements are not routinely available, technically demanding, and lacks broad standardization for clinical use. The bilirubin-to-albumin (B/A) ratio may provide a pragmatic intermediate marker, as it partly reflects bilirubin-binding capacity, but its clinical value is limited by variability in albumin binding and the influence of illness severity, acidosis, and competing substances. Therefore, despite its limitations, TSB levels remain the practical standard for treatment decisions. But clinically relevant analytical bias remains an important limitation of TSB measurements, emphasizing that the reliability of the assay is as important as the choice of biomarker.