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HYPERBILIRUBINEMIA, an elevated serum bilirubin. In humans, daily bilirubin production from all sources averages 250-300 mg, of which 85% is derived from the breakdown of senescent red cells in the mononuclear phagocytic (RE) system, especially in the spleen, liver, and bone marrow. The remaining 15% is produced from erythrocyte precursors destroyed in the bone marrow and from catabolism of other heme-containing proteins such as myoglobin, cytochromes, and peroxidases. Transport of bilirubin requires that it be tightly bound to albumin.

Nascent unconjugated bilirubin is virtually insoluble in aqueous solutions at the normal pH of blood. Unconjugated bilirubin refers to that bilirubin which is bound tightly to albumin prior to entering the liver. The albumin-bilirubin complex enters the liver and attaches to a hepatocyte receptor allowing bilirubin to enter the cell and albumin to reenter the circulation. In the hepatocyte, bilirubin undergoes a series of reactions with glucuronyl transferases becoming bilirubin glucuronides. This glucuronidation is required to convert bilirubin into a water soluble, non toxic pigment. This is referred to as conjugated bilirubin. There are at least four species of conjugated bilirubin found in serum.

To determine if the elevation is from conjugated or unconjugated bilirubin, urinalysis testing is required. Bilirubinuria is indicative of conjugated hyperbilirubinemia. Whereas, hyperbilirubinemia without bilirubinuria is diagnostic of unconjugated hyperbilirubinemia.  Isolated unconjugated hyperbilirubinemia may be secondary to hemolysis, Crigler-Najer disease, or Gilbert's disease. Therefore a CBC and a reticulocyte count should be obtained. If there is evidence of hemolysis, then this should be worked-up further. If there is no evidence of hemolysis, then Gilbert's disease is the likely etiology. If there is a direct hyperbilirubinemia without other abnormalities of the liver panel, then Dubin-Johnson syndrome or Rotor syndrome are the likely causes. If hyperbilirubinemia is associated with other abnormalities on the liver panel (transaminasemia or cholestasis), then the work-up of the other abnormalities takes precedence as that will most likely lead to the appropriate etiology quicker.

Mild hyperbilirubinemia is often asymptomatic except for the symptoms of the underlying cause. Moderate to severe hyperbilirubinemia manifests as jaundice and pruritus.  Severe hyperbilirubinemia often occurs when there is an hepatic source of the bilirubinemia in conjunction with renal failure.