Crigler-Najjar Syndrome

A congenital disorder characterized by unconjugated hyperbilirubinemia.

Bilirubin Uridine-Diphosphate Glucuronyltransferase Deficiency; Hereditary Unconjugated Hyperbilirubinemia.

Type I: Bilirubin Glucuronyltransferase Deficiency; Congenital Hyperbilirubinemia; Congenital Familial Nonhemolytic Jaundice.

Type II: Arias Syndrome.

Not precisely known but estimated to be approximately 1:1,000,000 live births, with approximately 120 cases with Crigler-Najjar syndrome type I described in the literature. No racial or sexual predilection has been reported.

Crigler-Najjar syndrome type I is an autosomal recessive inherited disorder with a mutation in the uridine diphosphate glucuronyltransferase (UGT)-1 gene located on 2q37. Crigler-Najjar syndrome type II, which is much more frequent than type I, is autosomal recessive inherited with a mutation mapping to the UGT-2 gene also on 2q37. Autosomal dominant forms have also been reported.

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). Uridine diphosphate glucuronyltransferases (UGT) are enzymes that detoxify numerous compounds by conjugating them with glucuronic acid and rendering them water soluble and harmless at the same time (glucuronidation). Crigler-Najjar syndrome type I is characterized by complete absence of bilirubin UGT, which leads to unconjugated hyperbilirubinemia with total serum bilirubin levels greater than 340 μmol/liter (20 mg/dl). In Crigler-Najjar syndrome type II, a partial deficiency of bilirubin UGT occurs with total serum bilirubin concentrations in the range from 100 to 340 μmol/liter (6-20 mg/dl). Because of residual enzyme activity in type II, phenobarbital treatment can be used to induce the enzyme and lower serum bilirubin concentration significantly.

In Crigler-Najjar syndrome type I, biliary bilirubin concentration is decreased and bilirubin glucuronide is absent. The diagnosis is confirmed by decreased glucuronyltransferase activity on the liver biopsy specimen. In contrast to Crigler-Najjar syndrome type II, there is no response to treatment with phenobarbital. Neonatal jaundice presenting soon after birth and lasting longer than 13 days in the absence of hemolysis may point to the diagnosis. The stool color often is pale yellow. Untreated, survival past the neonatal period is uncommon. Persistent jaundice during the neonatal period occurs in Crigler-Najjar syndrome type II, however, the levels of total bilirubin are significantly lower and generally neurologic symptoms do not appear. Confirmation of the diagnosis also requires a liver biopsy specimen to measure enzyme activity. Biliary bilirubin is (sub)normal, and stool color is normal.

Crigler-Najjar syndrome type I. Severe unconjugated hyperbilirubinemia with intense jaundice appears in the first 3 days of life and persists through the neonatal period. Diffusion of unconjugated (lipid-soluble) bilirubin into the brain may be favored by a damaged blood-brain barrier (e.g., hypoxia, hyperosmolality), but also by prematurity and the presence of hypoalbuminemia or highly protein-bound drugs (e.g., sulfonamides). Kernicterus usually presents in the first week of life (although it may occur at any time, especially during the neonatal period, but is not limited to this period) with lethargy, loss of the Moro reflex, and poor feeding. Left untreated, it may progress to opisthotonus, signs of increased intracranial pressure (e.g., bulging fontanelle, high-pitched crying), seizures, and stiffness. Affected infants often die in the first weeks or months of life secondary to kernicterus, others survive with little or no neurologic sequelae. In survivors, these neurologic signs often do not resolve or recur after an initial improvement and may finally result in bilateral choreoathetosis, seizures, mental retardation, hearing loss, speech anomalies, and extrapyramidal signs. The neurologic sequelae reflects injury to basal ganglia, corpus subthalamicum, thalamus, globus pallidum, putamen, cerebellar and cranial nerve nuclei, and hippocampal structures. Phototherapy (450-nm wavelength light) and emergent exchange transfusion often are required in the first days of life. The only treatment for Crigler-Najjar syndrome type I is liver transplantation.

Crigler-Najjar syndrome type II is most often benign, presenting with unconjugated hyperbilirubinemia in the first 3 days of life. It sometimes mimics physiologic neonatal icterus, however, persistence for more than 2 weeks should raise suspicion for Crigler-Najjar syndrome type II. Very rarely, kernicterus with bilirubin encephalopathy occurs in these patients (again, not confined to the neonatal period). Acute exacerbations can be associated with trauma, infection, anesthesia, or drugs, and plasmapheresis and/or exchange transfusion have been used successfully for treatment. Clinical signs of neurologic involvement may include mental retardation, seizures, and movement disorders.

Evaluate hepatic function (no coagulation disorders have been reported in this syndrome). Exclude a possible association with hemolysis. Correction of hypoalbuminemia should help reduce the concentration of free bilirubin. Evaluate plasma levels of bilirubin and glucuronyl transferase activity. Review electroencephalograms to evaluate preoperative brain function (seizures). If the patient is on phototherapy (some patients are on lifelong daily phototherapy for up to 20 hours per day), it should be continued as long as possible preoperatively and restarted postoperatively as soon as possible. In some cases, phototherapy has been used intraoperatively, particularly for longer procedures.

Keep fasting times as short as possible because it can increase bilirubin serum concentration. Acute exacerbations may be triggered by infections, so elective procedures should be postponed until the infection has been cured. Severe hypertension, hypercarbia, hyperosmolality, and acidosis should all be avoided because they may favor the passage of albumin-bound bilirubin through the blood-brain barrier. It is important to avoid hepatotoxic drugs and drugs that may displace bilirubin from its binding to serum proteins, thus increasing the risk of brain damage. Regional anesthesia is a safe alternative.

Thiopental can be used in both types of the disease, even in type I, although it does not decrease bilirubin levels. Midazolam is best avoided because of its linkage to plasma proteins and its possible interaction with bilirubin transport. For neuromuscular blockade, succinylcholine, atracurium, and cisatracurium are the drugs of choice. If possible, halogenated inhalational agents should be avoided, although desflurane, sevoflurane, and isoflurane are considered acceptable. Some cephalosporins and contrast media for radiologic procedures are contraindicated because of their extensive albumin binding with displacement of bilirubin from albumin. Morphine can be used because it is metabolized by a different glucuronyl transferase system.

Gilbert Syndrome: A benign inherited disorder characterized by chronic intermittent jaundice (unconjugated hyperbilirubinemia) that does not lead to particular complications and is not progressive (normal life expectancy; may even prolong life by preventing heart attacks).