Understanding Neonatal Jaundice: A Perspective on Causation

Abstract

Neonatal jaundice can be best understood as a balance between the production and elimination of bilirubin, with a multitude of factors and conditions affecting each of these processes. When an imbalance results because of an increase in circulating bilirubin (or the bilirubin load) to significantly high levels (severe hyperbilirubinemia), it may cause permanent neurologic sequelae (kernicterus). In most infants, an increase in bilirubin production (e.g., due to hemolysis) is the primary cause of severe hyperbilirubinemia, and thus reducing bilirubin production is a rational approach for its management. The situation can become critical in infants with an associated impaired bilirubin elimination mechanism as a result of a genetic deficiency and/or polymorphism. Combining information about bilirubin production and genetic information about bilirubin elimination with the tracking of bilirubin levels means that a relative assessment of jaundice risk might be feasible. Information on the level of bilirubin production and its rate of elimination may help to guide the clinical management of neonatal jaundice.

Etiologies and Initial Evaluation of Neonatal Jaundice

“…Physiologic neonatal jaundice encompasses three major mechanisms [1][2][3] of hyperbilirubinemia in the newborn: reduced conjugation, increased enterohepatic circulation, and increased production of bilirubin. Almost all newborns have decreased conjugation and excretion processes at birth [2], due to the low activity of UDP-glucuronosyltransferase (UGT) in hepatocytes and a paucity of intestinal flora that convert bilirubin to urobilinogen, resulting in increased enterohepatic circulation.…”

“…Almost all newborns have decreased conjugation and excretion processes at birth [2], due to the low activity of UDP-glucuronosyltransferase (UGT) in hepatocytes and a paucity of intestinal flora that convert bilirubin to urobilinogen, resulting in increased enterohepatic circulation. Moreover, fetal red blood cells turn over more frequently than do adult red blood cells [4][5][6], resulting in a shorter life span and more heme degradation in neonates.…”

“…Inability to substantially upregulate glucuronidation as in Gilbert's syndrome, and Crigler-Najjar (extremely rare), also presents at 3-7 days of life with indirect hyperbilirubinemia [2], as does breastfeeding failure jaundice. In Crigler-Najjar syndrome type 1, there is complete absence of UDP glucuronosyltransferase activity, and the result is bilirubin encephalopathy in the first days to months of life [11].…”

“…Neonates with Gilbert's syndrome have mildly decreased activity of UDP-glucuronosyltransferase,4 as well as deficient hepatic uptake of unconjugated bilirubin, both of which lead to indirect hyperbilirubinemia. Of note, Gilbert's syndrome coupled with glucose-6-phosphate dehydrogenase deficiency compounds the likelihood of severe indirect hyperbilirubinemia [2,12,13]. Breastfeeding failure jaundice arises from lactation failure resulting in reduced oral intake for the neonate.…”

“…With the exception of breast milk jaundice (which peaks at 2 weeks), neonatal jaundice beyond the first 14 days of life is very often a result of direct hyperbilirubinemia [2,3], for which there exist two classes of etiologies: hepatic and post-hepatic causes. The hepatic causes of direct hyperbilirubinemia encompass metabolic and infectious entities including: Dubin-Johnson and Rotor syndromes, cystic fibrosis, alpha 1-antitrypsin deficiency, galactosemia, ToRCHeS infections, viral hepatitis, and neonatal sepsis.…”