Glucuronyl Transferase Deficiency Treatment & Management

Treatment of patients with Crigler-Najjar (CN) syndrome is not limited to phototherapy, phenobarbital therapy, or both. Response to treatment varies according to the type of Crigler-Najjar syndrome.

Crigler-Najjar syndrome type 1 does not respond to phenobarbital therapy, and patients may require repeated exchange transfusions followed by long-term phototherapy to prevent neurologic complications. Other therapies include plasmapheresis, hemoperfusion, cholestyramine, calcium phosphate, and oral agar. An approach to therapy using Sn-protoporphyrin, a heme oxygenase inhibitor, was introduced to prevent an increase in serum bilirubin levels.^[8] In patients with Crigler-Najjar syndrome type 1, liver transplantation remains the only guaranteed form of therapy.

In contrast, Crigler-Najjar syndrome type 2 responds favorably to phenobarbital therapy. A favorable response to phenobarbital supports the diagnosis of Crigler-Najjar syndrome type 2. However, rarely, patients with Crigler-Najjar syndrome type 2 may require exchange transfusions or long-term phototherapy.

• Phototherapy

  • Phototherapy has been successful in controlling bilirubin levels for years.
  • Phototherapy causes the formation of water-soluble bilirubin isomers that can be secreted in bile without conjugation.
  • Patients with Crigler-Najjar syndrome type 1 generally need 10-16 hours of treatment per day. Monitor the intensity of light to a level of at least 4-10 µW/cm²/nm. The appropriate wave length is in the blue-green spectrum at 425-475 nm.
  • The efficacy of phototherapy is dose dependent; therefore, the response to phototherapy increases when the dose is increased. Efficacy of phototherapy can be increased by increasing the intensity of light, by increasing exposure of body surface, and by using reflecting surfaces (eg, mirrors).
  • Double-surface phototherapy has also been used in some cases to improve the outcome.
  • The effectiveness of phototherapy decreases with increasing patient age, and the need for alternative therapy increases.
  • Newer methods of delivering phototherapy, such as sit-up phototherapy units, may reduce phototherapy time by 50% while maintaining effectiveness and, thus, may allow a child to attend school.
  • Long-term phototherapy may lead to developmental delay, impaired weight gain, and possible psychological disturbances.
  • Problems associated with phototherapy include decreased effectiveness with age, restriction of activity and play, poor compliance, inability of the patient to travel or take vacations, irritation from the eye shades, difficulties in temperature maintenance, tanning of the skin, embarrassment from the need to be nearly nude during phototherapy, and difficulty in procuring phototherapy lamps.
• Exchange transfusion

  • Exchange transfusion is used in Crigler-Najjar syndrome type 1 to lower unconjugated bilirubin levels to a safe level to prevent kernicterus.
  • Treatment with exchange transfusions and phototherapy should be intensified early to prevent kernicterus due to high levels of unconjugated bilirubin.
• Gene therapy^[9]

  • Gene therapy offers the greatest potential for cure for patients with Crigler-Najjar syndrome. Successful cloning of the gene responsible for bilirubin glucuronosyltransferase activity offers the hope of future gene therapy to correct this deficiency.
  • Clinically significant improvement can be achieved, even with partial enzyme replacement.
  • Only about 5% of normal uridinediphosphoglucuronate glucuronosyltransferase (UGT) 1A1 can significantly lower the plasma bilirubin concentration and decrease the need for phototherapy.
  • Studies of the Gunn rat (deficient in all members of the UGT 1A family) showed long-term correction of hyperbilirubinemia with one injection of helper-dependent adenoviral vectors.^[5] This effect has yet to be proven in humans.

• Liver transplantation

  • Liver transplantation remains the sole definitive treatment.^{[10, 11]} Cadaveric orthotopic or auxiliary and living related liver transplantation has resulted in excellent survival rates and prognoses.
  • Patients with Crigler-Najjar syndrome type 1 are ideal candidates for auxiliary liver transplantation.
  • Early liver transplantation in patients with Crigler-Najjar syndrome type 1 decreases the incidence of neurologic deficits, especially for patients in whom reliable administration of phototherapy cannot be guaranteed.
• Hepatocyte transplantation^{[12, 13, 14]}

  • Hepatocyte transplantation involves catheterization of the portal vein and an infusion of donor hepatocytes.
  • The immunosuppression regimen is similar to that administered to patients receiving whole-organ transplantation and currently includes tacrolimus and prednisolone.
  • Stem cells and stem cell–derived hepatocytes should offer the potential to overcome the current limitations of both the supply of hepatocytes and the extent of repopulation of the liver after transplantation.^[15]
  • Hepatocyte transplantation has been reported to decrease the need for phototherapy and to increase the activity of UGT to 5.5% of normal.