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

PATHOPHYSIOLOGY

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 neurotoxicity is mediated through a variety of mechanisms, including impaired mitochondrial function, DNA and protein synthesis, and synaptic transmission. Factors that increase bilirubin neurotoxicity include the concentration of bilirubin and the duration of exposure to it, albumin levels, and conditions that increase blood-brain barrier permeability (e.g. infection, acidosis, hyperoxia, sepsis, prematurity, hyperosmolarity).⁵

Jaundice, the yellow discoloration of the skin and sclerae, may be present at birth or appear any time in the first month of life. It generally starts on the face and spreads down the body in a cephalocaudal progression. Unconjugated bilirubin in the skin appears bright yellow or orange, whereas conjugated bilirubin appears more greenish or muddy yellow; these may be difficult to detect in darker-skinned infants. The extent of cephalocaudal jaundice progression has a poor overall accuracy for predicting risk of significant hyperbilirubinemia, and therefore should not be used to estimate bilirubin level; however, complete absence of jaundice is helpful in predicting which infants will not develop significant hyperbilirubinemia.⁶ Infants who are jaundiced secondary to insufficient milk intake may also be dehydrated, appear lethargic, and have significant weight loss (>10% of birth weight), dry mucous membranes, poor capillary refill, sunken eyes and fontanelle, and poor skin turgor.

Signs of acute bilirubin encephalopathy usually appear 2 to 5 days after birth but may occur any time during the neonatal period. In the early phase, infants display lethargy, hypotonia, and poor ability to suck. In the intermediate phase, infants have stupor, irritability, and hypertonia (retrocollis-opisthotonos) alternating with drowsiness and hypotonia. They may also develop a fever and high-pitched cry. Infants who reach the late phase may have increased retrocollis-opisthotonos, cessation of feeding, bicycling movements, inconsolable irritability and crying, seizures, fever, and coma. Many of these infants die, and the survivors are likely to have severe kernicteric sequelae, even after intensive treatment. The rate of progression of clinical signs depends on the rate of bilirubin rise, duration of hyperbilirubinemia, host susceptibility, and presence of comorbidities.⁵

Infants who survive acute bilirubin encephalopathy may have kernicteric sequelae such as extrapyramidal movement disorders (dystonia and athetosis), gaze abnormalities (especially upward gaze), auditory disturbances (especially sensorineural hearing loss with central processing disorders or auditory neuropathy), and enamel dysplasia of the deciduous teeth. Cognitive deficits are unusual. Earlier reports of mental retardation in children with kernicterus probably reflected an inability to accurately assess intelligence in children with hearing, communication, and coordination problems.

The distinction between physiologic jaundice and pathologic jaundice relates to the timing, rate of rise, and extent of hyperbilirubinemia, as some of the same causes of physiologic jaundice (e.g. large red blood cell mass, decreased capacity for bilirubin conjugation, increased enterohepatic circulation) can also result in pathologic jaundice. Jaundice appearing in the first 24 hours of life and bilirubin levels that exceed 17 mg/dL or rise more than 5 mg/dL per day should be considered pathologic, and a specific cause should be sought. Direct bilirubin fractions greater than 10% of the total bilirubin should also be considered abnormal.

The differential diagnosis for pathologic jaundice is extensive (Table 130-1). Processes that lead to increased bilirubin production include isoimmune hemolysis (due to ABO, Rh, or other minor blood group incompatibility), extravascular hemolysis (cephalohematoma and skin bruising), polycythemia, and glucose-6-phosphate dehydrogenase (G6PD) deficiency. Genetic and metabolic disorders resulting in decreased uptake, storage, or metabolism of bilirubin include Crigler-Najjar syndrome (I or II), Gilbert syndrome, Lucey-Driscoll syndrome, hypothyroidism, and hypopituitarism. These rare disorders should be considered when bilirubin levels are greater than 10 mg/dL beyond the first week of life. Processes that result in increased enterohepatic circulation, such as breastfeeding and intestinal obstruction, may also cause pathologic jaundice. Breastfeeding is one of the strongest risk factors for significant hyperbilirubinemia. Infants who are breastfed have higher average peak bilirubin levels than do formula-fed infants. The hyperbilirubinemia observed with breastfeeding is likely multifactorial in origin. Decreased milk intake before maternal milk production is established results in dehydration, which hemoconcentrates bilirubin. Poor milk intake results in fewer bowel movements, which in turn increases the enterohepatic circulation of bilirubin.

Breastfeeding jaundice, which occurs in the first week of life, should be distinguished from breast milk jaundice, which refers to the jaundice that persists beyond the first week of life in approximately 2% of breastfed infants. With breast milk jaundice, bilirubin levels can rise as high as 10 to 30 mg/dL in the second to third week and then decrease, but jaundice may persist for up to 10 weeks. Discontinuation of breastfeeding and substitution of formula for 1 to 2 days results in a rapid and sustained decline in serum bilirubin, but this is generally not recommended unless bilirubin levels approach treatment thresholds. The cause of breast milk jaundice is not known with certainty, although β-glucuronidase (resulting in deconjugation of bilirubin and increased enterohepatic circulation) and other factors in breast milk that might interfere with bilirubin conjugation (e.g. pregnanediol and free fatty acids) have been implicated as potential causes.