G6PD is the most common red cell enzyme deficiency, occurring most commonly in infants of Mediterranean, Middle Eastern, African, and Southeast Asian descent. This disorder occurs in up to 15% of African American newborns. The mode of inheritance is X-linked recessive. Presence of this deficiency confers resistance against Plasmodium falciparum, the infectious agent causing malaria. G6PD generates substrates that protect the red cell against oxidative stress. Erythrocytes lacking these substrates undergo hemolysis with oxidative stress. Important triggers in the neonate include sepsis or exposure to other stressors (naphthalene, sulfa drugs, acetaminophen, breast milk of a mother who has eaten fava beans, etc.). However, the pathogenesis of hyperbilirubinemia appears to be more complicated than simple hemolysis. Often, the offending agent is not identified, and infants with significant hyperbilirubinemia have no evidence of hemolysis, leading some authorities to postulate a concurrent impairment in bilirubin conjugation or clearance. Classically, hyperbilirubinemia appears between 24 and 96 hours postpartum, and it can be severe, even in the absence of significant anemia. Up to 50% of patients also have Gilbert syndrome (see later), and this combination increases the risk of hyperbilirubinemia and kernicterus. Many states include G6PD in the routine newborn screen. In the 2004 American Academy of Pediatrics (AAP) guidelines for hyperbilirubinemia, the committee emphasized the possibility for the underdiagnosis of G6PD deficiency in the newborn period, and encouraged practitioners to consider this diagnosis in infants with the appropriate ethnic backgrounds who are poor responders to phototherapy.

Deficiency in pyruvate kinase causes ineffective adenosine triphosphate generation from glucose, resulting in shortened red cell survival. This disorder is inherited in an autosomal recessive pattern and is most common in whites of northern European descent. Clinical expression ranges from severe neonatal jaundice to compensated hemolytic anemia.

Defects that affect the red cell membrane and cytoskeletal structure alter the shape and deformability of the cell and result in hemolysis and hyperbilirubinemia. Conditions include hereditary spherocytosis, elliptocytosis, and pyknocytosis.

With an incidence of 1 in 5,000, hereditary spherocytosis is the most common congenital RBC membrane disorder. This disease is inherited in an autosomal
dominant manner, with 25% of cases arising from new mutations. Family history can be significant for splenectomy, gallstones, and anemia. Increased RBC Load Any condition that results in increased RBC load can result in hyperbilirubinemia secondary to breakdown of extravascular or sequestered erythrocytes. Common conditions include cephalohematoma, extensive bruising after traumatic delivery, and polycythemia.

Macrosomic infants of insulin-dependent diabetic mothers represent a unique group of patients at risk for hyperbilirubinemia. These infants have high levels of erythropoietin and increased erythropoiesis; thus ineffective red cell production and polycythemia are probably responsible for the resulting hyperbilirubinemia.

Type I is a rare disease that results from an autosomal recessive inheritance of a deficiency in UDPGT activity. These patients develop severe hyperbilirubinemia in the first 2 to 3 days of life and often require exchange transfusion. Patients with type II disease (also known as Arias syndrome) retain some UDPGT activity, and infants typically have less severe hyperbilirubinemia. Furthermore, infants with type II disease are also partially responsive to phenobarbital, which induces enzyme activity.

Gilbert syndrome affects 5% to 10% of the general population, and both autosomal dominant and recessive patterns of inheritance are described. Infants may have mildly elevated levels of unconjugated bilirubin when compared to controls because of decreased UGT1 activity. Presentation with pathologic hyperbilirubinemia in the newborn period is rare, unless a concurrent condition such as G6PD deficiency or hereditary spherocytosis exists.

Lucey-Driscoll syndrome can be associated with significant hyperbilirubinemia and is thought to be related to a hormone or antibody from the maternal serum that inhibits the action of UDPGT. This is a self-limited process and should be considered in unexplained familial severe hyperbilirubinemia.