Unbound (Free) Bilirubin: Improving the Paradigm for Evaluating Neonatal Jaundice

Abstract

Background: The serum or plasma total bilirubin concentration (BT) has long been the standard clinical laboratory test for evaluating neonatal jaundice, despite studies showing that BT correlates poorly with acute bilirubin encephalopathy (ABE) and its sequelae including death, classical kernicterus, or bilirubin-induced neurological dysfunction (BIND). The poor correlation between BT and ABE is commonly attributed to the confounding effects of comorbidities such as hemolytic diseases, prematurity, asphyxia, or infection. Mounting evidence suggests, however, that BT inherently performs poorly because it is the plasma non–protein-bound (unbound or free) bilirubin concentration (Bf), rather than BT, that is more closely associated with central nervous system bilirubin concentrations and therefore ABE and its sequelae. Content: This article reviews (a) the complex relationship between serum or plasma bilirubin measurements and ABE, (b) the history underlying the limited use of Bf in the clinical setting, (c) the peroxidase method for measuring Bf and technical and other issues involved in adapting the measurement to routine clinical use, (d) clinical experience using Bf in the management of newborn jaundice, and (e) the value of Bf measurements in research investigating bilirubin pathochemistry. Summary: Increasing evidence from clinical studies, clinical experience, and basic research investigating bilirubin neurotoxicity supports efforts to incorporate Bf expeditiously into the routine evaluation of newborn jaundice. .

Neonatal bilirubin binding capacity discerns risk of neurological dysfunction

“…A low Alb level and a high bilirubin/Alb ratio are recommended risk factors for BIND in recognition that binding status is a concern in the management of newborn jaundice (2,(6)(7)(8). However, the variation in the BBC/Alb among infants has been pointed out as the reason for caution in the use of the Alb level and bilirubin/Alb molar ratio as quantitative indicators of binding status in BIND risk assessment (2,4,(6)(7)(8). Thus, a direct measure of BBC should be advantageous.…”

“…As pointed out by McDonagh and Maisels (24), a renewed availability of hematofluorometry should facilitate such studies. Ahlfors et al (1,4,20) make the case that the UB/TB ratio, which reflects both the RABC and the binding affinity (UB/TB = 1/(K × RABC), should be a better indicator of risk for BIND than either UB or TB alone because the UB/TB should better reflect the extravascular bilirubin load. The UB/TB ratio is also indicative of the rate of rise of UB for an incremental rise in TB.…”

“…The long-standing belief that total serum/ plasma bilirubin (TB), by itself, does not reliably predict an infant's risk for developing bilirubin-induced neurological dysfunction (BIND) or kernicterus has been recently reconfirmed (2)(3)(4)(5). The traditional reliance on the TB level alone as a clinical measure of both bilirubin exposure and risk for neurotoxicity may result in overuse of phototherapy or delayed phototherapy in cases where exposure risk is underestimated.…”

“…However, neither serum Alb levels nor the molar ratio of TB to Alb has been predictive of bilirubin neurotoxicity (4,(6)(7)(8). BBC, when directly measured by various methods, is generally lower than that expected from the Alb level, especially in preterm and sick infants in whom the ratio of capacity to Alb is highly variable (9,10).…”

“…While an assay of serum/plasma unbound or "free" bilirubin (UB) to predict the risk of BIND has been employed for many years by researchers (8), it generally remains a research tool. The role of UB as a unique clinical biomarker of BIND has not been fully elucidated (2,4,8). However, sufficient bench data has accumulated to suggest that dynamic UB is "buffered" by an infant's BBC (4).…”