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Kernicterus, or chronic bilirubin encephalopathy, is a permanent and devastating condition associated with significant mortality, morbidity, and intellectual disability. The risk for development of kernicterus in otherwise healthy newborns is increased with severe neonatal hyperbilirubinemia, or total serum bilirubin values >20 mg/dL.1 A systematic approach to the detection and management of hyperbilirubinemia in newborns is therefore critical for prevention. While kernicterus in the United States is a rare condition, with an estimated incidence of 1.5 per 100,000 full-term newborns, the diagnosis of hyperbilirubinemia is far more common, affecting over 15% of full-term infants and nearly 60% of preterm infants in the first 30 days of life.2 Hyperbilirubinemia is the most common neonatal condition requiring extension of the newborn hospital stay or readmission to the hospital after newborn discharge.3


Bilirubin is a breakdown product of heme, which is contained primarily in hemoglobin but also in myoglobin and cytochromes. Microsomal heme oxygenase catabolizes heme to biliverdin, which is then reduced to bilirubin by biliverdin reductase. The resulting unconjugated biliruibin is a non-polar, lipid-soluble molecule that is transported to the liver in plasma bound to albumin. In the endoplasmic reticulum of the hepatocytes, bilirubin uridine diphosphate glucuronosyl transferase (UDPGT) conjugates bilirubin with glucuronic acid. Conjugated bilirubin is a polar, water-soluble molecule that is excreted from the hepatocyte to the bile canaliculi, through the biliary tree, and into the duodenum. In the colon, bacterial β-glucuronidase converts conjugated bilirubin to urobilinogen. A small amount of urobilinogen is absorbed and returned to the liver (enterohepatic circulation) or excreted by the kidneys. The rest is converted to stercobilin and excreted in the feces.

Hyperbilirubinemia is classified as either conjugated or unconjugated (also known as direct or indirect, referring to the van den Bergh reaction used to measure bilirubin). Unconjugated hyperbilirubinemia is caused by increased production, decreased hepatic uptake or metabolism, or increased enterohepatic circulation of bilirubin. Newborn infants are particularly susceptible to unconjugated hyperbilirubinemia because, compared with adults; they have more red cells with a higher turnover and a shorter life span, and a limited ability to conjugate bilirubin. Newborn bilirubin levels typically peak on days 3 to 5 of life at about 5 to 6 mg/dL and then decrease over the next few weeks to adult levels. Exaggerated physiologic jaundice occurs at values above this threshold (7 to 17 mg/dL). Bilirubin levels higher than 17 mg/dL are not generally considered physiologic, and a cause of pathologic jaundice should be sought.4

Conjugated hyperbilirubinemia can occur with hepatocellular or cholestatic disease that causes a decreased secretion of bilirubin into the canaliculi or decreased drainage through the biliary tree.

Unconjugated bilirubin that exceeds the binding threshold of albumin (maximum of 8.2 mg bilirubin per gram of albumin) enters the brain and deposits primarily in neurons in the basal ganglia, hippocampus, cerebellum, and brainstem nuclei for oculomotor function and hearing. Bilirubin’s ...

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