Crigler-Najjar Syndrome

At a glance

A congenital disorder characterized by unconjugated hyperbilirubinemia.

Synonyms

Bilirubin Uridine-Diphosphate Glucuronyltransferase Deficiency; Hereditary Unconjugated Hyperbilirubinemia.

Classification

There are two types of this medical condition:

• Crigler-Najjar Syndrome Type I (CN1): Bilirubin Glucuronyltransferase Deficiency; Congenital Hyperbilirubinemia; Congenital Familial Nonhemolytic Jaundice.

• Crigler-Najjar Syndrome Type II (CN2): Arias Syndrome.

People affected with CN1 have functionally no enzyme activity, whereas those affected with CN2 have less than 20% of normal enzyme activity.

Incidence

It affects approximately 1:1,000,000 live births. No racial or sexual predilection has been reported.

Genetic inheritance

CN1 is an autosomal recessive inherited disorder with deleterious mutations (nonsense or stop codons) in the UGT1A1 (Uridine Diphosphate Glucuronyltransferase 1A1) gene located on chromosome 2q37.1. The much more frequent CN2 is also autosomal recessive inherited with a mutation mapping to the UGT-2 gene located on the same chromosome as CN1. However, unlike CN1, the genetic defect in CN2 is usually caused by a point mutation resulting in a single amino acid substitution, thus enzyme activity is reduced, but not completely absent as in CN1. Autosomal dominant forms have occasionally been reported.

Pathophysiology

This enzymopathy affects the conjugation of bilirubin with glucuronic acid. Unconjugated bilirubin has the ability to penetrate into the neonatal brain and cause neurologic damage and encephalopathy (kernicterus). Before entering the hepatocytes, bilirubin dissociates from albumin. Once inside the hepatocyte, bilirubin binds to ligandin, an intracytoplasmic transporter protein that transfers bilirubin to the smooth endoplasmic reticulum, where glucuronidation takes place. Uridine diphosphate glucuronyltransferases are enzymes that detoxify numerous compounds by conjugating them with glucuronic acid and rendering them water soluble and harmless at the same time (glucuronidation). UGT1A1 is a transmembrane protein that has a binding site for bilirubin and another one for uridine diphosphate glucuronic acid. In a first step, UGT1A1 catalyzes the transfer of one glucuronic acid molecule onto bilirubin (bilirubin-monoglucuronide) and in a second step adds another glucuronic acid molecule to form bilirubin-diglucuronide, both water-soluble so they can be excreted in the bile. CN1 is characterized by complete absence of bilirubin-UGT isoform A1A and leads to unconjugated hyperbilirubinemia with total serum bilirubin levels greater than 340 µmol/L (20 mg/dL). In CN2, a partial deficiency of bilirubin UGT occurs with total serum bilirubin concentrations in the range of 100 to 340 µmol/L (6-20 mg/dL). Due to residual enzyme activity in CN2, phenobarbital treatment can be used to induce the enzyme and lower serum bilirubin concentration significantly.

Diagnosis

In CN1, the biliary bilirubin concentration is decreased and bilirubin glucuronide is absent. The diagnosis is confirmed by decreased glucuronyltransferase activity in a liver biopsy specimen. In contrast to CN2, there is no response to treatment with phenobarbital. Neonatal ...