Development of Bilirubin Production by Heme Catabolism
Bilirubin is formed in the organism by oxidation–reduction reactions. It is the end product of heme catabolism (Figure 5-1). The heme comes mainly from aging red blood cells (RBCs), but muscle myoglobin and some liver enzymes such as cytochromes and catalases are a partial source.1 Production of erythrocytes is first observed in the fetal yolk sac at 2–3 weeks of gestation. RBC production in the liver is seen at about 6 weeks of gestation and in the marrow at 20 weeks.2 The mean life span of RBCs in the term newborn infant is around 45–90 days, and about 35–50 days in premature infants.3 Fetal and adult hemoglobin are structurally different. Together with a higher hemoglobin concentration, this explains the increased oxygen-carrying capacity in the fetus. Postnatally, these mechanisms are no longer needed. Production of adult hemoglobin starts in the last trimester of pregnancy, and in the absence of certain hemoglobinopathies the production of fetal hemoglobin is turned off at birth.3
Diagram of bilirubin metabolism. Fe2+, iron; CO, carbon monoxide; UDPGT (UGT), uridine diphosphoglucuronyltransferase.
Bilirubin-IXβ appears in the human fetus at 14 weeks of gestation.4 Two weeks later unconjugated bilirubin-IXα appears in bile. By 20 weeks of gestation IXα constitutes 6% of bilirubin in bile, IXβ 87%, IXγ 0.5%, and IXδ 6%.5 By 38 weeks gestation, bilirubin-IXα has replaced IXβ as the main isomer.4
In fetal hemolytic disease, such as Rhesus immunization, the concentration of total serum bilirubin (TSB) can increase from 1.5 mg/dL at 20 weeks of gestation to 4.1 mg/dL at 32 weeks. Weiner described an inverse relationship between TSB and hemoglobin concentrations.6 Thus, when fetuses became severely anemic (hematocrit <30), 82% had TSB concentrations exceeding the 97.5th percentile on the Bhutani nomogram.7 Increased TSB could be detected weeks before the development of anemia. A TSB >3 mg/dL was associated with a high likelihood of severe fetal anemia. Goodrum et al. studied the effect of repeated intrauterine transfusions and found a mean TSB value of 5.6 mg/dL (1.3–10.8 mg/dL) at the time of the third transfusion, almost all unconjugated.8 Thus, although bilirubin can pass the placenta (see below), fetal hemolytic disease is accompanied by fetal hyperbilirubinemia. It therefore appears that the placenta has a limited capacity for transfer of bilirubin, which is exceeded in fetal hemolytic disease.
The first step in the breakdown of heme is catalyzed by heme oxygenase (HO), and is the rate-limiting step in heme degradation (Figure 5-1).9,10 This enzyme is found in the reticuloendothelial system, and also in tissue macrophages and in gut mucosa.11 Formation of biliverdin is an intermediate step in bilirubin production. Because carbon monoxide (CO) is a by-product of this process, measurement of CO in exhaled breath, corrected for ambient CO (ETCOc), can be used ...