Toward Understanding Kernicterus: A Challenge to Improve the Management of Jaundiced Newborns

Abstract

Experimental and clinical data strongly suggest that measurement of Bf in newborns with hyperbilirubinemia will improve risk assessment for neurotoxicity, which emphasizes the need for additional clinical evaluation relating Bf and TSB to acute bilirubin toxicity and long-term outcome. We speculate that establishing risk thresholds for neurotoxicity by using newer methods for measuring Bf in minimally diluted serum samples will improve the sensitivity and specificity of serum indicators for treating hyperbilirubinemia, thus reducing unnecessary aggressive intervention and associated cost and morbidity.

Calculated free bilirubin levels and neurotoxicity

“…Furthermore, assuming that at a hazardous TSB level of 35 mg per 100 ml the calculated serum B F concentration is approximately equal to the CNS B F concentration (at this level there may be rapid equilibration of bilirubin between serum and brain 1,27-29 ), calculated CNS B F levels ( Table 2) would range from 375 to 2751 nM depending on the human bilirubin-albumin binding constant and the serum albumin concentrations assumed for the calculation. The calculated CNS B F levels at a TSB of 35 mg per 100 ml shown in Table 2 are representative of a range of reported human serum bilirubin-albumin binding constants 3,23 and albumin concentrations most likely to be encountered in the clinical arena. It is notable that there is considerable overlap and remarkable similarity between the calculated human CNS B F values and those calculated for saline-treated hyperbilirubinemic homozygous Gunn rat pups with cerebellar hypoplasia (Figure 1).…”

“…The concentration of this 'free' bilirubin (B F ) is believed to dictate the biologic effects of bilirubin in jaundiced newborns, including its neurotoxicity. [1][2][3] The threshold at which B F produces changes in cellular function culminating in permanent cell injury and cell death has been the subject of considerable debate and study for some time. Recently, Daood and Watchko 4 calculated central nervous system (CNS) B F levels in Gunn rat pups during peak postnatal hyperbilirubinemia (day of life 15 to 19) 5,6 and correlated those levels with the cerebellar weights and neurobehavioral status of the pups.…”

“…The representativeness of these findings is limited by their postmortem nature and possible further diffusion of bilirubin into the CNS tissue following the infant's demise, that is, postmortem artifact. Indeed, CNS B F levels derived from the Claireaux brain bilirubin data, calculated assuming a 'corrected' CNS albumin concentration term comparable with that of Gunn rat pups and using a reported range of human albumin-bilirubin binding constants, 3,23 are exceedingly high, approximating 27 000 nM. An alternative approach is needed to explore the potential calculated neurotoxic CNS B F level(s) in human neonates.…”

“…Moreover, the calculated neurotoxic B F levels approximate the threshold serum concentration of unbound bilirubin, measured by a peroxidase method, reported to induce neurological deficits in a teenage patient with Crigler-Najjar type I syndrome, 30 if the reported unbound values are corrected for measurement conditions, namely sample dilution. 3,[31][32][33][34] Measured unbound levels associated with neurological deficits in this patient exceeded 20 nM; actual unbound bilirubin corrected for the B40-fold sample dilution used in the measurement 35 is typically at least 10-fold higher, 31 resulting in a predicted serum B F associated with abnormal neurological signs in this patient of >200 nM. Another report on a teenage patient with Crigler-Najjar syndrome observed the onset of neurological abnormalities at a serum B F of 46.7 nM (B467 nM predicted if corrected for sample dilution) with a return to normal status at a serum B F of 16.1 nM (B161 nM predicted if corrected for sample dilution).…”

“…3,23,[31][32][33][34] Among other factors, k varies as a function of sample dilution, albumin concentration, albumin species and the study medium including the presence of competing compounds. 3,23,[31][32][33][34] In this regard, the very low albumin concentration (3 mM) in the CNS of Gunn rat pups 4 relative to that in serum would be predicted to significantly increase the apparent bilirubin-albumin binding constant k (relative to serum) 33 and result in a lower calculated CNS B F than that reported using serum k values. 4 However, this effect is most likely countered, even offset, by the greatly decreased number of bilirubin-binding sites associated with the markedly lower CNS albumin concentration.…”