The objectives of this chapter are to review the causes of direct hyperbilirubinemia/neonatal cholestasis as well as to provide a step-wise approach to the evaluation and management of neonates with conjugated hyperbilirubinemia.
Jaundice is a common finding in neonates, with as many as 50% of infants having transient jaundice in the first 5 days of life. Neonatal jaundice lasting greater than 2–3 weeks requires additional evaluation as it may suggest cholestasis, a condition that is not normal at any age.
Conjugated hyperbilirubinemia is defined as direct bilirubin level greater than 2 mg/dL or 20% of the total bilirubin. Conjugated hyperbilirubinemia is caused by cholestasis—the pathologic reduction in bile formation or flow. Cholestasis may be caused by hepatocellular injury, obstruction to bile flow, or the presence of bile canalicular transport defects. Newborns are particularly prone to developing cholestasis because of the liver’s immature excretory capacity.
Many disease processes can cause neonatal cholestasis and often these diseases lack specific diagnostic testing, making the evaluation of neonatal cholestasis complex. Table 40.1 provides a complete list of differential diagnoses to consider in infants with neonatal cholestasis and the diagnostic evaluation for each diagnosis. However, a few conditions account for most cases of neonatal cholestasis. In term infants, over 70% of the cases of cholestasis are caused by neonatal hepatitis and biliary atresia (BA), while α1-antitrypsin (A1AT) deficiency accounts for 5–15% of the cases. In contrast, cholestasis in premature infants is often caused by prolonged parenteral nutrition or sepsis. Refer to Table 40.2 for a list of the most common causes of neonatal cholestasis in term infants.
TABLE 40.1.Causes of Neonatal Cholestasis and Diagnostic Approach ||Download (.pdf) TABLE 40.1. Causes of Neonatal Cholestasis and Diagnostic Approach
| ||Disease ||Key Diagnostic Strategy |
|Anatomic || |
Inspissated bile syndrome
Neonatal sclerosing cholangitis
Spontaneous perforation of bile duct
Delayed or absent excretion on hepatobiliary scan, biliary obstruction on histology
|Infectious || |
Herpes simplex virus
HHV-6, herpes zoster
Enteric viral sepsis (echoviruses, Coxsackie A and B viruses, adenoviruses)
Urinary tract infection
Urine, blood, or CSF for viral culture or PCR within 2–4 weeks of birth, hearing test
STS, VDRL, FTA-ABS
Anti-HIV immunoglobulins, CD4 count
HBV panel, HBV DNA
HCV RNA PCR
Serologies, CSF for viral studies
|Metabolic || |
Disorders of carbohydrate metabolism
Type IV glycogen storage disease
Disorders of amino acid metabolism
Disorders of lipid metabolism
Niemann-Pick, type A
Niemann-Pick, type C
Disorders of bile acid synthesis
Other metabolic defects
Galactose-1-6-phosphate uridyl transferase
Liver biopsy: ...