Predominantly Unconjugated Hyperbilirubinemia

Excess production of bilirubin

••Hemolytic anemias

••Resorption of blood from internal hemorrhage (e.g., alimentary tract bleeding, hematomas)

••Ineffective erythropoiesis syndromes (e.g., pernicious anemia, thalassemia)

Reduced hepatic uptake

••Drug interference with membrane carrier systems

••Some cases of Gilbert syndrome

Impaired bilirubin conjugation

••Physiologic jaundice of the newborn (decreased UGT1A1 activity, decreased excretion)

••Breast milk jaundice (b-glucuronidases in milk)

••Genetic deficiency of UGT1A1 activity (Crigler-Najjar syndrome types I and II)

••Gilbert syndrome (mixed etiologies)

••Diffuse hepatocellular disease (e.g., viral or drug-induced hepatitis, cirrhosis)

Predominantly Conjugated Hyperbilirubinemia

Deficiency of canalicular membrane transporters (Dubin-Johnson syndrome, Rotor syndrome)

Impaired bile flow

UGT, uridine diphosphate-glucuronyltransferase.

Neonatal Jaundice.

Because the hepatic machinery for conjugating and excreting bilirubin does not fully mature until about 2 weeks of age, almost every newborn develops transient and mild unconjugated

hyperbilirubinemia, termed neonatal jaundice or physiologic jaundice of the newborn. Breast-fed infants tend to exhibit jaundice with greater frequency, possibly the result of b-

glucuronidases present in maternal milk. These enzymes deconjugate bilirubin glucuronides in the gut, increasing intestinal reabsorption of unconjugated bilirubin. Sustained jaundice in

the newborn is indicative of a disease condition, discussed later under neonatal hepatitis.

Hereditary Hyperbilirubinemias.

In rare instances, there may be a genetic lack of UGT1A1 ( Table 18-4 ). In Crigler-Najjar syndrome type I, the enzyme is completely absent. Multiple genetic defects in the locus coding

for UGT1A1 may give rise to this disorder.[10] The liver is incapable of synthesizing a functional enzyme, and the colorless bile contains only trace amounts of unconjugated bilirubin. The

liver is morphologically normal by light and electron microscopy. However, serum unconjugated bilirubin reaches very high levels, producing severe jaundice and icterus. Without liver

transplantation, this condition is invariably fatal, causing death within 18 months of birth secondary to kernicterus.

Crigler-Najjar syndrome type II is a less severe, nonfatal disorder in which UGT1A1 enzyme activity is greatly reduced, and the enzyme is capable of forming only monoglucuronidated

bilirubin. Unlike Crigler-Najjar syndrome type I, the only major consequence is extraordinarily yellow skin from moderate to high levels of circulating unconjugated bilirubin;

phenobarbital treatment can improve bilirubin glucuronidation by inducing hypertrophy of the hepatocellular endoplasmic reticulum. Mutations either reduce the affinity of UGT1A1

toward bilirubin or reduce enzyme activity.[11] Almost

TABLE 18-4-- Hereditary Hyperbilirubinemias

Disorder Inheritance Defects in Bilirubin Metabolism Liver Pathology Clinical Course

Date: 2016-04-22; view: 711