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Inborn Metabolic Disorders Causing Hyperbilirubinemia

By

Danielle Tholey

, MD, Thomas Jefferson University Hospital

Last full review/revision Oct 2019| Content last modified Oct 2019
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Hereditary or inborn metabolic disorders may cause unconjugated or conjugated hyperbilirubinemia (see Overview of bilirubin metabolism).

  • Unconjugated hyperbilirubinemia: Crigler-Najjar syndrome, Gilbert syndrome, and primary shunt hyperbilirubinemia

  • Conjugated hyperbilirubinemia: Dubin-Johnson syndrome and Rotor syndrome

Crigler-Najjar Syndrome

This rare inherited liver disorder is caused by deficiency of the enzyme glucuronyl transferase (UGT1A1), which catalyzes the conjugation of bilirubin (mainly to bilirubin diglucuronide) to render bilirubin water soluble. Various defects in the gene coding for the enzyme cause complete (type 1) or partial (type 2) inactivation of the enzyme.

Patients with autosomal recessive type I (complete) disease have severe unconjugated hyperbilirubinemia typically beginning shortly after birth. They usually die of kernicterus by age 1 year but may survive into adulthood. Treatment may include phototherapy and liver transplantation.

Patients with autosomal recessive type II (partial) disease (which has variable penetrance) often have less severe unconjugated hyperbilirubinemia (< 20 mg/dL [< 342 micromol/L]) and usually live into adulthood without neurologic damage. Phenobarbital 1.5 to 2 mg/kg orally 3 times/day, which induces the partially deficient glucuronyl transferase, may be effective.

Dubin-Johnson Syndrome and Rotor Syndrome

Dubin-Johnson syndrome and Rotor syndrome cause conjugated hyperbilirubinemia, but without cholestasis, causing no symptoms or sequelae other than jaundice. Bilirubin may appear in the urine, in contrast to the unconjugated hyperbilirubinemia in Gilbert syndrome (which also causes no other symptoms), in which bilirubin is absent from 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 syndrome

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

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, red blood cell destruction is also slightly accelerated, but this acceleration does not cause anemia or 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 micromol/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 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.

Primary Shunt Hyperbilirubinemia

This rare, familial, benign condition is characterized by overproduction of early-labeled bilirubin (bilirubin derived from ineffective erythropoiesis and nonhemoglobin heme rather than from normal red blood cell turnover).

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