Bilirubin produced after hemoglobin catabolism is lipid soluble and unconjugated and reacts as an indirect reagent in the van den Bergh test. Indirect-reacting, unconjugated bilirubin is toxic to the central nervous system and is insoluble in water, limiting its excretion. Unconjugated bilirubin binds to albumin on specific bilirubin binding sites; 1 g of albumin binds 8.5 mg of bilirubin in a newborn. If the binding sites become saturated or if a competitive compound binds at the site, displacing bound bilirubin, free bilirubin becomes available to enter the central nervous system. Organic acids such as free fatty acids and drugs such as sulfisoxazole can displace bilirubin from its binding site on albumin.
Bilirubin dissociates from albumin at the hepatocyte and becomes bound to a cytoplasmic liver protein Y (ligandin). Hepatic conjugation results in the production of bilirubin diglucuronide, which is water soluble and capable of biliary and renal excretion. The enzyme glucuronosyltransferase represents the rate-limiting step of bilirubin conjugation. The concentrations of ligandin and glucuronosyltransferase are lower in newborns, particularly in premature infants, than in older children.
Conjugated bilirubin gives a direct reaction in the van den Bergh test. Most conjugated bilirubin is excreted through the bile into the small intestine and eliminated in the stool. Some bilirubin may undergo hydrolysis back to the unconjugated fraction by intestinal glucuronidase, however, and may be reabsorbed (enterohepatic recirculation). In addition, bacteria in the neonatal intestine convert bilirubin to urobilinogen and stercobilinogen, which are excreted in urine and stool and usually limit bilirubin reabsorption. Delayed passage of meconium, which contains bilirubin, also may contribute to the enterohepatic recirculation of bilirubin.
Bilirubin is produced in utero by the normal fetus and by the fetus affected by erythroblastosis fetalis. Indirect, unconjugated, lipid-soluble fetal bilirubin is transferred across the placenta and becomes conjugated by maternal hepatic enzymes. The placenta is impermeable to conjugated water-soluble bilirubin. Fetal bilirubin levels become only mildly elevated in the presence of severe hemolysis, but may increase when hemolysis produces fetal hepatic inspissated bile stasis and conjugated hyperbilirubinemia. Maternal indirect (but not direct) hyperbilirubinemia also may increase fetal bilirubin levels.
Etiology of Indirect Unconjugated Hyperbilirubinemia Decision-Making Algorithm
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Physiologic jaundice is a common cause of hyperbilirubinemia among newborns. It is a diagnosis of exclusion, made after careful evaluation has ruled out more serious causes of jaundice, such as hemolysis, infection, and metabolic diseases. Physiologic jaundice is the result of many factors that are normal physiologic characteristics of newborns: increased bilirubin production resulting from an increased RBC mass, shortened RBC life span, and hepatic immaturity of ligandin and glucuronosyltransferase. Physiologic jaundice may be exaggerated among infants of Greek and Asian ancestry.