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Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia.

• Unconjugated hyperbilirubinemia: Gilbert syndrome, Crigler-Najjar syndrome, and primary shunt hyperbilirubinemia
• Conjugated hyperbilirubinemia: Dubin-Johnson syndrome and Rotor's syndrome

Gilbert Syndrome

Gilbert syndrome is a presumably lifelong disorder in which the only significant abnormality is asymptomatic, mild, unconjugated hyperbilirubinemia. It can be mistaken for chronic hepatitis or other liver disorders. Gilbert syndrome may affect as many as 5% of people. Although family members may be affected, a clear genetic pattern is difficult to establish.

Pathogenesis may involve complex defects in the liver's uptake of bilirubin. Glucuronyl transferase activity is low, though not as low as in Crigler-Najjar syndrome type II. In many patients, RBC destruction is also slightly accelerated, but this acceleration does not explain hyperbilirubinemia. Liver histology is normal.

Gilbert syndrome is most often detected in young adults serendipitously by finding an elevated bilirubin level, which usually fluctuates between 2 and 5 mg/dL (34 and 86 μmol/L) and tends to increase with fasting and other stresses.

Gilbert syndrome is differentiated from hepatitis by fractionation that shows predominantly unconjugated bilirubin, otherwise normal liver function test results, and absence of urinary bilirubin. It is differentiated from hemolysis by the absence of anemia and reticulocytosis. Treatment is unnecessary. Patients should be reassured that they do not have liver disease.

Crigler-Najjar Syndrome

This rare inherited disorder is caused by deficiency of the enzyme glucuronyl transferase. Patients with autosomal recessive type I (complete) disease have severe hyperbilirubinemia. They usually die of kernicterus by age 1 yr but may survive into adulthood. Treatment may include phototherapy and liver transplantation. Patients with autosomal dominant type II (partial) disease (which has variable penetrance) often have less severe hyperbilirubinemia (< 20 mg/dL [< 342 μmol/L]) and usually live into adulthood without neurologic damage. Phenobarbital Some Trade Names
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1.5 to 2 mg/kg po tid, which induces the partially deficient glucuronyl transferase, may be effective.

Primary Shunt Hyperbilirubinemia

This rare, familial, benign condition is characterized by overproduction of early-labeled bilirubin.

Dubin-Johnson Syndrome and Rotor's Syndrome

Dubin-Johnson syndrome and Rotor's syndrome cause conjugated hyperbilirubinemia, but without cholestasis, causing no symptoms or sequelae other than jaundice. In contrast to unconjugated hyperbilirubinemia in Gilbert syndrome (which also causes no other symptoms), bilirubin may appear in the urine. Aminotransferase and alkaline phosphatase levels are usually normal. Treatment is unnecessary.

Dubin-Johnson syndrome: This rare autosomal recessive disorder involves impaired excretion of bilirubin glucuronides. It is usually diagnosed by liver biopsy; the liver is deeply pigmented as a result of an intracellular melanin-like substance but is otherwise histologically normal.

Rotor's syndrome: This rare disorder is clinically similar to Dubin-Johnson syndrome, but the liver is not pigmented, and other subtle metabolic differences are present.

Last full review/revision July 2009 by Steven K. Herrine, MD

Content last modified July 2009