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Jaundice that persists or recurs during the second week of life requires inquiry. Frequently, such jaundice is caused by elevation of the unconjugated, or indirect, bilirubin and is often the result of a benign process. More concerning is jaundice caused by elevation of the conjugated bilirubin fraction. Neonatal cholestasis is caused by an accumulation of biliary substances, such as bilirubin and bile acids, because of impaired canalicular bile flow. Manifestations of conjugated hyperbilirubinemia must be differentiated from unconjugated hyperbilirubinemia because it is more often associated with a specific disease process (Figure 98-1). The medical management of cholestasis is largely supportive because the underlying disease is often untreatable medically. Such treatment addresses complications of chronic cholestasis rather than the underlying cause. These complications include malabsorption, nutritional deficiencies, and pruritus.


An approach to a neonatal intensive care unit patient with conjugated hyperbilirubinemia. ALT, alanine transferase; AST, aspartate transferase; GGT, γ-glutamyl transpeptidase; PFIC, progressive familial intrahepatic cholestasis; T4, thyroid hormone, thyroxine; TB, total bilirubin; TCB, transcutaneous bilirubin; TORCH, toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus; TSH, thyroid-stimulating hormone


Levels of Hyperbilirubinemia

  1. Direct bilirubin greater than 10% of total bilirubin (TB; < 5 mg/dL)

  2. Conjugated bilirubin greater than 1 mg/dL (TB < 5 mg/dL)

  3. Direct bilirubin greater than 20% of TB (TB > 5 mg/dL)

  4. Conjugated bilirubin greater than 2 mg/dL (TB > 5 mg/dL)

Clinical Risk Factors for Hyperbilirubinemia

The Cholestasis Guideline Committee recommended that any infant noted to be jaundiced at 2 weeks of age be evaluated for cholestasis with measurement of total and direct serum bilirubin.

Clinical Manifestations

  1. Onset of jaundice after the first weeks of age should be considered abnormal.

  2. Persistence of jaundice after 2 weeks of age should be considered abnormal.

  3. Association of pale stools or dark urine should be an alert for cholestasis.


The most commonly used laboratory determination (the diazo or van den Bergh method) does not specifically measure conjugated bilirubin but reports direct bilirubin. For methodological reasons, the higher the total bilirubin (even if it is all unconjugated) value, the higher the reported direct bilirubin will be. Measurements of direct bilirubin may vary significantly both within and between laboratories.


Table 98-1 provides information on the differential diagnosis of conjugated hyperbilirubinemia.

Table 98-1Differential Diagnosis of Conjugated Hyperbilirubinemia

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