Bilirubin is formed by the destruction of both erythropoietic heme and nonerythropoietic heme. Erythropoietic heme, derived from the destruction of red blood cells, accounts for 85% of the total bilirubin. Nonerythropoietic heme is derived from the breakdown of proteins such as myoglobin, catalase, tryptophan pyrrolase, and cytochromes. The breakdown of heme is catalyzed by heme oxygenase in the presence of cytochrome P-450. Heme oxygenase is produced in greater amounts during times of stress, such as fasting. Bilirubin is conjugated in the microsomes of the smooth endoplasmic reticulum to two molecules of glucuronide. Glucuronide is made by uridine diphosphate glucose (UDPG) dehydrogenase. Conjugated (direct) bilirubin is then excreted into the bile and subsequently into the intestines, where bacteria transform it into urobilinogen.

In both physiologic jaundice and breast milk jaundice, the level of indirect (unconjugated) bilirubin is elevated.
This fraction of bilirubin is not measured, so its value is obtained by subtracting the value for direct bilirubin from the value for total bilirubin. The value for direct bilirubin is normal in all cases of physiologic and breast milk jaundice. Physiologic jaundice is thought to be caused by delayed conjugation and increased turnover of hemoglobin, in addition to an immature secretory system within the liver (biliary tract) and an immature excretory system outside the liver (intestines). The exact cause of breast milk jaundice is unknown. The elevated levels of 5β-pregnane-3α, 20β-diol, or nonesterified long-chain fatty acids found in some maternal breast milk, in addition to glucuronidase, may interfere with the glucuronidation of bilirubin.

Hemolytic anemia leads to indirect hyperbilirubinemia because the production of heme-activated heme oxygenase leads to an increase in bilirubin. In addition, conjugation is slower in infants because of their low levels of UDPG dehydrogenase. Hemolytic anemia has been associated with blood group incompatibilities, hereditary hemolytic syndromes, and neonatal infections of bacterial or viral origin.

Genetic enzyme defects are responsible for syndromes such as Crigler-Najjar syndrome types I and II and Gilbert syndrome. Both types of Crigler-Najjar syndrome are caused by an absence of uridine diphosphate (UDP) glucuronosyltransferase; the inheritance is autosomal recessive. Gilbert syndrome is caused by a deficiency of UDP glucuronosyltransferase; the inheritance is autosomal dominant with incomplete penetrance.

All infants with the disorders described in the preceding text appear jaundiced to varying degrees. Infants with physiologic jaundice or breast milk jaundice appear healthy, without signs of lethargy or organomegaly. The timing and degree of jaundice and a history of breast-feeding can often differentiate the two. The urine is normal in color because the unconjugated bilirubin is not water soluble. The stool does not become acholic in color because excretion of conjugated bilirubin occurs. Jaundice rarely appears during the first 36 hours of life. The bilirubin levels often peak by day 4 to 6 of life, with maximum levels of 6 to 12 mg/dL in physiologic jaundice. In breast milk jaundice, the peak bilirubin level can be as high as 20 mg/dL and usually appears by day 5 to 6 of life. Jaundice associated with hemolytic anemia appears within the first 36 hours of life and may be associated with hydrops fetalis or hepatosplenomegaly.

Crigler-Najjar syndrome is associated with an early rapid rise in bilirubin that if left untreated results in neurologic devastation (kernicterus). The urine color is pale. In addition, because conjugated bilirubin is not excreted, the stools are clay-colored. A therapeutic trial of phenobarbital causes the bilirubin level to drop in patients with type II Crigler-Najjar syndrome but not in those with type I.

In patients with Gilbert syndrome, the bilirubin levels rise to a point of clinical detection during physiologic stress, such as fasting and intercurrent illness. Gilbert syndrome is more common in boys, with a male-to-female ratio of 2:1 to 7:1.

Red flags for neonatal unconjugated hyperbilirubinemia are as follows:

If an infant is jaundiced beyond 2 weeks of age, the total and direct bilirubin levels should be measured. If the direct component is <15% of the total and the total bilirubin is elevated, indirect hyperbilirubinemia is diagnosed. A positive Coombs test result identifies a problem with isoimmunization that can be associated with:

If the Coombs test result is negative, then other causes should be sought (Table 8.1).

The goal of treatment is to avoid the most serious complication of indirect hyperbilirubinemia, kernicterus. Various treatments include phototherapy, exchange transfusion, enzyme induction, alteration of breast-feeding, and interruption of the enterohepatic circulation. In breast milk jaundice, withholding breast-feeding for 1 to 3 days should result in a reduction of the total bilirubin level >50%. Phototherapy changes the course of indirect hyperbilirubinemia by converting the insoluble form of bilirubin to a water-soluble, nontoxic form, lumirubin that can be excreted in the urine.

The treatment of Crigler-Najjar type II disease is phenobarbital, which may lower the bilirubin to acceptable levels. In both types I and II, long-term phototherapy may be required. If phototherapy is not applied consistently in type I disease, kernicterus may develop. Liver transplantation is an accepted and recommended therapy for type I disease because of the high level of associated morbidity and quality-of-life issues related to daily night-time phototherapy.

The prognosis for patients with uncomplicated physiologic jaundice, breast milk jaundice, and Gilbert syndrome are excellent, with no long-term sequelae. If kernicterus develops, the infant will have severe mental and motor retardation. If liver transplantation is performed for Crigler-Najjar type I disease, the chance of a normal life expectancy is better than 85%, and further phototherapy is not needed. However, these patients will require long-term immunosuppression.

Cholestatic liver disease in infants has numerous causes. The overall incidence is approximately 1 in 2500 live births. The two most common causes of neonatal cholestasis are neonatal hepatitis (idiopathic) and biliary atresia. Other causes, in decreasing frequency, are listed in Table 8.2.

The intrahepatic cholestatic syndromes include diseases such as Alagille syndrome, Byler disease (PFIC1), and other bile acid defect syndromes (e.g., bile salt export pump [BSEP] deficiency, multidrug resistance [MDR]3 deficiency, and 3β-hydroxysteroid dehydrogenase [3β-HSD]). Endocrine and metabolic defects that are associated with cholestasis include:

Idiopathic neonatal hepatitis can occur in either a sporadic or a familial form. Cholestasis develops in the central zones within hepatocytes and canaliculi, but rarely in the bile ducts. Prominent giant cell transformation and extramedullary hematopoiesis are characteristic. No steatosis is noted on liver biopsy specimens.

Extrahepatic biliary atresia is a progressive, sclerosing, inflammatory process that can affect any portion of the extrahepatic biliary tree. Segmental or complete obliteration of the ductular lumen leads to rapid progression to endstage liver disease. The two types of presentation are related to the underlying cause of the disease. The fetal form is possibly caused by an unknown gene mutation because laterality anomalies are often associated. The perinatal form (most common) is probably secondary to an insult, such as a viral infection.

Abnormalities typically associated with extrahepatic biliary atresia include:

α₁-Antitrypsin deficiency is inherited as an autosomal-recessive condition. Liver disease associated with α₁-antitrypsin deficiency occurs in patients with the PiZZ phenotype, although on rare occasions it may be associated with
PiZS and PiZ null. Liver damage is thought to be caused by the accumulation of an abnormal α₁-antitrypsin gene product within the hepatocytes. Histologically, the liver biopsy reveals giant cells, extramedullary hematopoiesis, hepatocellular cholestasis and plugs in the canaliculi, periodic acid-Schiff-positive and diastase-resistant eosinophilic globules.

Two types of bile duct paucity syndromes are associated with neonatal cholestasis: Alagille syndrome (arteriohepatic dysplasia) and nonsyndromic bile duct paucity syndrome. On microscopy, the two appear identical and can be differentiated only by the associated abnormalities seen in patients with Alagille syndrome. Under the light microscope, both diseases are characterized by a paucity of bile ducts (<0.5 ducts/portal triad). As a result, bile cannot be adequately drained from the liver.

Abnormalities associated with Alagille syndrome include: