Chapter 19: Hyperbilirubinemia

I. Intensive care

1. Definition

   1. Jaundice

      1. Jaundice (as distinct from hyperbilirubinemia) relates to the yellow color produced in the sclera, skin, and subcutaneous tissues by deposition of bilirubin in those sites.

      2. Not all jaundiced newborns are necessarily hyperbiliru-binemic.

      3. Visual assessment of jaundice is an inaccurate way of determining whether a baby is actually hyperbilirubinemic, especially in a premature infant.

   2. Hyperbilirubinemia

      1. In term infants, hyperbilirubinemia is frequently defined as a serum total bilirubin (STB) concentration >95th percentile on the hour-specific bilirubin nomogram.

      2. In preterm infants, in contrast, there are no clear definitions of normal or physiologic bilirubin levels and hence of hyperbilirubinemia. The reasons for this are multifold.

         • Almost all preterm infants develop some degree of jaundice during the first postnatal days.

         • There are dynamic changes in STB levels during this period.

         • The significance of the jaundice with regard to bilirubin neurotoxicity may increase with decreasing gestational age.

         • Phototherapy is used frequently in these infants, thereby moderating STB values and preventing these from reaching natural peaks.

   3. Practical definitions

      1. For practical purposes in the preterm infant in the intensive care setting, we suggest the following, based on the indications for phototherapy and exchange transfusion:

         • Moderate hyperbilirubinemia: Includes any STB level meeting accepted criteria for phototherapy

         • Severe hyperbilirubinemia: Regarded as any STB meeting or exceeding the indications for exchange transfusion

2. Incidence

   1. Almost all premature infants develop some degree of increased STB concentration that may cause jaundice and, in some instances, hyperbilirubinemia.

      1. In the absence of specific criteria for hyperbilirubinemia, the incidence of the condition is difficult to determine.

      2. The majority of premature infants <1.5 kg birthweight will meet phototherapy requirements during the first postnatal week.

3. Pathophysiology

   1. Physiology of bilirubin metabolism

      The physiology of bilirubin is similar in the premature and term infant.

      1. Bilirubin formation

         Red blood cells are continually being broken down in the reticuloendothelial system and replaced. This process releases heme, which is catabolized by the enzyme heme oxygenase 1 to biliverdin and thence to bilirubin. This form of bilirubin is called unconjugated or indirect bilirubin. Bound to serum albumin the bilirubin is transported to the liver.

      2. Bilirubin conjugation and elimination

         After uptake into the hepatocyte, unconjugated bilirubin is glucuronated to form water soluble mono- and diglucuronides, known as conjugated or direct bilirubin. The enzyme controlling the conjugation process is UDP-glucuronosyltransferase 1A1 (UGT). Direct bilirubin is excreted via bile to the bowel from which it is excreted from the body.

      3. Genetic control of bilirubin conjugation

         The enzyme UGT1A1 is encoded by the gene UGT1A1. This gene contains a noncoding promoter region and a coding region. Polymorphisms of the promoter region, such as the (TA)_n polymorphism, result in diminished expression of a normally formed enzyme and are associated with Gilbert syndrome. Coding area mutations result in an abnormally structured enzyme with no or little conjugating ability, such as is seen in Crigler-Najjar syndrome.

      4. Enterohepatic circulation

         In the newborn bowel, conjugated bilirubin may be unconjugated by the enzyme ?-glucuronidase and reabsorbed into the ...