Bilirubin Photoisomers in Neonatal Jaundice

Abstract

Phototherapy is the standard treatment for neonatal hyperbilirubinemia. During phototherapy, the highly lipophilic bilirubin is converted into more hydrophilic photoisomers, which can be more easily excreted from the body. This process typically lowers bilirubin levels to non-harmful concentrations. However, despite decades of research into the formation and role of bilirubin photoisomers, methodological limitations and the compound's complex biochemistry have hindered comprehensive understanding. This review provides an updated overview of current knowledge on bilirubin photoisomers, including their basic chemistry, analytical quantification, clinical relevance, and future research directions. Improved insight into the mechanism of photoisomer formation and kinetics may inform optimization of phototherapy parameters, including light intensity and wavelength, and offer additional indicators of treatment efficacy beyond total bilirubin concentration. Advances in sensitive and standardized mass spectrometry techniques now enable more accurate measurement of different bilirubin isomers and serve as a first step towards a deeper insight into the clinical relevance of photoisomers.

Keywords: hyperbilirubinemia; mass spectrometry; newborn infant; photoisomers; phototherapy.

Figure 3

Absorption spectrum of unconjugated BR in chloroform [31,32]. Dashed gray lines indicate the wavelength used for PT in various studies (×: ref [25], +: ref [28]). The solid gray line with a white square displays the measured extinction coefficient at 440 nm in phosphate buffer pH 7.4 [33]. The spectrum was scaled to match the extinction coefficient of 50,000 M⁻¹ cm⁻¹ at 440 nm.

Figure 1

Structures and nomenclatures of some BR isomers. ZZ-BR (center), its asymmetry is highlighted with the endo-vinyl dipyrrinone to the left, and the exo-vinyl dipyrrinone to the right. Below, two enantiomeric conformers of ZZ-BR are depicted, formed through intramolecular hydrogen bonding. The top left depicts the configurational isomer ZE-BR with numbering and the E, Z configuration indicated. The top right depicts the constitutional isomer Z-LR, which contains two stereogenic centers (*), each producing an enantiomeric pair.

Figure 2

Schematic overview of the isomerization reactions occurring during PT. Solid arrows are of greater importance than dashed arrows. Black arrows and isomers are of higher importance than gray. (1) ZE-BR is the major photoisomer found in blood following PT [20]. (2) EZ-BR is of less importance due to slower formation rate and the practically irreversible nature of the conversion to Z-LR [10], making it more of an intermediate [21]. (3) Z-LR is more important due to its rapid excretion which makes it a major source of bilirubin reduction during PT [9]. (4) EE-BR is the thermodynamically least favorable of the configurational isomers [26], hence shifting the equilibrium largely towards EZ-BR and ZE-BR. (5) E-LR is less favorable for formation than Z-LR.