Etiology and Pathogenesis

Bilirubin is produced from the breakdown of heme. Heme is released from hemoglobin in the red blood cells (RBCs), metabolized to an intermediate product called biliverdin, and then metabolized further into unconjugated bilirubin, which circulates in the bloodstream primarily bound to albumin. Unconjugated bilirubin is then taken up by the liver, where it is bound to glucuronic acid by the enzyme uridine diphosphate glucuronyltransferase (UDPGT), creating water-soluble conjugated bilirubin, which can then be excreted into the gastrointestinal (GI) tract through the bile ducts. When stool has a delayed transit time, conjugated bilirubin can be broken down in the GI tract and reabsorbed into the bloodstream, a process known as enterohepatic circulation.

Most infants have at least a transient increase in their bilirubin levels in the first week of life, referred to as physiologic jaundice. This is attributable to relatively low activity of UDPGT at birth, large RBC mass, and the relatively short duration of survival of a newborn’s RBCs. Physiologic jaundice generally peaks during the first week of life, with levels rarely requiring treatment.

Because of multiple different etiologies, some infants develop more severe hyperbilirubinemia. Increased bilirubin production can occur in infants with increased RBC breakdown (G6PD [glucose-6-phosphate dehydrogenase] deficiency, ABO incompatibility, cephalohematoma) or elevated total body RBC stores (polycythemia, infants of diabetic mothers). Decreased bilirubin conjugation also contributes to hyperbilirubinemia in some infants because of decreased activity of UDPGT in Crigler-Najjar and Gilbert’s syndromes. Additionally, breastfeeding jaundice can occur early in the neonatal period in the setting of poor breast milk supply and associated dehydration and decreased stool output in an exclusively breastfed infant. In contrast, breast milk jaundice usually peaks during the second week of life and may take several more weeks to resolve completely. The mechanism of this process is not entirely understood but may involve components of breast milk inhibiting hepatic conjugating enzymes or increasing enterohepatic circulation. All of the aforementioned processes, because of their position in the bilirubin pathway, cause unconjugated hyperbilirubinemia (Box 100-1 and Figure 100-1).

Figure 100-1 Congenital and familial hyperbilirubinemias.

Conjugated hyperbilirubinemia occurs when the defective step exists after the conjugation of bilirubin, specifically involving defects in bile flow resulting in neonatal cholestasis (see Figure 100-1). The differential diagnosis of neonatal cholestasis is vast, including structural anomalies such as biliary atresia, choledochal cysts, and Alagille syndrome, metabolic disorders, including α-1 antitrypsin deficiency, galactosemia, and tyrosinemia, and endocrinopathies such as hypothyroidism (Figure 100-2). Additionally, infectious causes include viral (cytomegalovirus, HIV, herpes simplex virus), and bacterial (sepsis, urinary tract infections), and parasitic infections have been associated with conjugated hyperbilirubinemia. Other causes of conjugated hyperbilirubinemia include inherited deficiencies in excretion (Dubin-Johnson and Rotor’s syndromes), chromosomal disorders, parenteral nutrition, vascular and neoplastic processes, and idiopathic neonatal hepatitis (see Box 100-1).

Figure 100-2 Biliary atresia and cholestasis.