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High-Yield Facts

  • Jaundice within the first 24 hours of life is NEVER normal.

  • Urinary tract infections can be associated with the onset of unconjugated hyperbilirubinemia after a week of age.

  • Conjugated hyperbilirubinemia is never normal at any age, consider hemolytic disease with unconjugated hyperbilirubinemia beyond the neonatal period.

  • Acute cholangitis should be suspected in any patient with fever and jaundice who has had surgical correction of biliary atresia


Hemoglobin released from red blood cells is broken down into heme, and reduced to unconjugated (indirect) bilirubin which is then bound to serum albumin. Unconjugated bilirubin is converted to water-soluble conjugated (direct) bilirubin in the liver and stored in the gallbladder as bile. Bile is released into the intestines to assist in digestion and cholesterol metabolism as well as absorption of lipids and fat-soluble vitamins. Hyperbilirubinemia can be due to an increase in either unconjugated bilirubin or conjugated bilirubin levels. Conditions causing increased red blood cell destruction or decreased conjugation lead to unconjugated hyperbilirubinemia. Conditions that impair secretion of bile from liver or gallbladder result in conjugated hyperbilirubinemia.

The patient's age and the type of hyperbilirubinemia, whether direct or indirect, are important factors in determining the cause and treatment.

Neonatal Unconjugated Hyperbilirubinemia

The most common causes of indirect/unconjugated hyperbilirubinemia in the first week of life are physiologic jaundice, breast milk jaundice, and hemolysis.

Physiologic neonatal jaundice becomes visible by second or third day peaking by the fourth day and decreasing by seventh day of life. Physiologic jaundice is due to increased production of bilirubin following breakdown of fetal RBCs combined with limited conjugation of bilirubin by the liver. In full-term infants, 6% to 7% have indirect bilirubin levels greater than 12.9mg/dL and less than 3% will have levels greater than 15mg/dL.1

Breast milk jaundice is a common cause of neonatal unconjugated hyperbilirubinemia. It is due to beta-glucuronidases and nonesterified fatty acids in breast milk that inhibit enzymes which conjugate bilirubin. Bilirubin levels peak at 2 to 3 weeks of life, may remain elevated for 3 weeks to 2 months and then resolve.

Birth trauma resulting in cephalhematomas, bruising that leads to excessive red cell breakdown, and maternal-fetal blood group incompatibility such as Rh/ABO incompatibility can cause excessive red cell destruction and resultant hyperbilirubinemia.2 Erythrocyte enzymatic defects such as G6PD and pyruvate kinase deficiency decrease RBC life span and cause hemolysis. Infections can impair hepatic conjugation leading to unconjugated hyperbilirubinemia. Disorders of hepatic uptake and conjugation such as Gilberts and Crigler–Najjar syndrome also lead to unconjugated bilirubinemia. In infants with pyloric stenosis, 10% to 25% develop jaundice due to impaired conjugation which corrects rapidly after surgery. Endocrine disorders such as congenital hypothyroidism cause impaired conjugation leading to jaundice.2 (Fig. 73-1).


Neonatal unconjugated hyperbilirubinemia.

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