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Imbalance between Bilirubin Production and Elimination

The total serum bilirubin (TSB) concentration at any point in time reflects a multiplicity of interactions leading to two major processes contributing to this value: bilirubin production and bilirubin elimination.1 As long as these processes remain in equilibrium, the TSB should remain within normal limits. During the first days of life, because of physiologically increased heme catabolism in combination with diminished activity of the bilirubin conjugating enzyme, UDP-glucuronosyltransferase 1A1 (UGT1A1), there is an imbalance between these processes and bilirubin levels increase. In the majority of cases, this imbalance should remain mild or moderate, and TSB concentrations should not exceed the 95th percentile on the hour-of-life-specific bilirubin nomogram.2 When the rate of bilirubin production exceeds elimination (the latter process dependent primarily on conjugation), hyperbilirubinemia occurs. Although in many (perhaps most) cases, hyperbilirubinemia is associated with some degree of increased heme catabolism, severe hemolysis is not essential to the process. More important is the concept of lack of equilibrium between bilirubin production and conjugation. Thus, a baby may be hemolyzing and producing large amounts of bilirubin, but because hepatic bilirubin conjugating capacity is mature, the infant may not develop an increased TSB. On the other hand, a baby with minimally increased hemolysis, but with immature bilirubin conjugating capacity (due to late prematurity or the presence of the (TA)7 repeat UGT1A1 gene promoter polymorphism, associated with Gilbert syndrome), may develop hyperbilirubinemia. This concept of equilibrium, or lack thereof, between bilirubin production and conjugation has been demonstrated mathematically. Kaplan et al. studied the individual contributions of bilirubin production and conjugation to the TSB concentration, as well as the combined effects of these processes in healthy, term neonates on the third day of life.3 The rate of heme catabolism was indexed by measurements of blood carboxyhemoglobin (COHb) determinations, corrected for ambient carbon monoxide (COHbc), while bilirubin conjugation was assessed by total serum conjugated bilirubin (TCB) expressed as a percentage of TSB (TCB(%)). Over the range of TSB concentrations observed, TSB correlated with both increasing COHbc levels and diminishing TCB(%) values (Figure 8-1A and B). The COHbc and TCB(%) values were then used to construct an index or ratio, COHbc/TCB(%), to reflect the combined forces of these processes. The correlation of this “production–conjugation index” with increasing TSB concentrations was higher than that for either COHbc or TCB(%), independently (Figure 8-2). Thus, the concept of imbalance and interaction between bilirubin production and conjugation, rather than individual or independent processes, in the mechanism of neonatal bilirubinemia was confirmed. Although the relationship between the index and TSB tended to plateau with increasing index values, at the lower end of the index scale, which included the majority of readings, small increases in the index were associated with large increases in TSB.

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