Crigler-Najjar syndrome

Synonyms: Crigler-Najjar disease, Arias' syndrome (type II Crigler-Najjar syndrome)

What is Crigler-Najjar syndrome?

Crigler-Najjar syndrome is a rare autosomal recessive inherited non-haemolytic unconjugated hyperbilirubinaemia caused by uridine diphosphate glucuronosyltransferase deficiency, resulting in an impairment of the ability to conjugate and excrete bilirubin. There are two forms of this disorder:¹

• Type 1 disease is associated with severe jaundice and neurological impairment due to bilirubin encephalopathy that can result in permanent neurological sequelae.

• Type 2 disease is associated with a lower serum bilirubin concentration and affected patients survive into adulthood without neurological impairment.

There are mutations in the structure of the gene, whose locus is on the long arm of chromosome 2.^{2 3} This leads to either virtually absent enzyme activity (type I) or impaired activity (type II).

UGT1A1 is the only enzyme catalysing the generation of water-soluble bilirubin glucuronides in hepatocytes. Therefore, mutations in this gene lead to deficiencies in bilirubin conjugation and excretion.⁴

Classification of Crigler-Najjar syndrome^{4 5}

Crigler-Najjar syndrome involves two very rare autosomal recessive disorders (types I and II), which differ in the degree of UGT1A1 deficit and consequently in the clinical presentation.⁶ Crigler-Najjar syndrome affects 0.6-1 in 1 million newborns around the world.¹

Type I

• Very rare. Absent or nearly absent UGT1A1 enzyme activity.

• Presents shortly after birth with serum bilirubin levels greater than 20-50 mg/dL.

• Absence of bilirubin glucuronides in bile.

• It is associated with bilirubin encephalopathy and death unless managed by aggressive phototherapy and exchange transfusions in the immediate newborn period.

• The risk for kernicterus persists into adult life.

• Phenobarbital has no effect on bilirubin levels.

Type II (Arias' syndrome)

• More common than type I but still rare. Reduced (but not abolished) UGT1A1 enzyme activity (<10% of normal).

• Predominantly autosomal recessive inheritance.

• Unconjugated hyperbilirubinaemia occurs in the first days of life but total bilirubin levels usually do not exceed 20 mg/dL. Bilirubin glucuronides present in bile.

• Type II rarely results in kernicterus. In older children and adults, illness and stress may cause temporary increases in bilirubin levels.

• Phenobarbital reduces bilirubin levels by about 30%.

How common is Crigler-Najjar syndrome? (Epidemiology)⁷

• It is extremely rare. The true incidence/prevalence are unknown.

• Type II appears to be more common than type I but it is still an unusual sporadic disease.

• Gilbert's syndrome is much more common.

• Isolation of parents and medical/allied professionals working in the field has been a bar to progress in treatment and research but is improving due to the institution of international conferences for all interested parties.

Symptoms of Crigler-Najjar syndrome (presentation)⁴

Type I

• Presents with persistent, marked jaundice at or soon after birth.

• Kernicterus may manifest as hypotonia, deafness, oculomotor palsies and ultimately death.

• If untreated, it causes death due to the kernicterus by the age of 2.

Type II

• Jaundice may occur in the newborn, in infancy or later in childhood.

• Jaundice may be precipitated by infection, anaesthesia or drug use.

• Bilirubin encephalopathy is rare but may be precipitated by sepsis, medications or other intercurrent illness.

Investigations

• Mutations in the UGT1 A1 gene that are known to cause the disorder can be detected by molecular genetic testing, although it can be done only at specialised laboratories.¹

• Total serum bilirubin is elevated with unconjugated (indirect) bilirubin predominating.

• Gross elevation of bilirubin at 290-855 μmol/L (17-50 mg/dL) in type I, milder elevation in type II at 100-375 μmol/L (6-22 mg/dL).

• Type II cases may show higher, more toxic levels of bilirubin during episodes of haemolysis, intercurrent illness or drug reactions.

• LFTs are usually otherwise normal.

Differential diagnosis

Other causes of neonatal jaundice, including:

• Gilbert's syndrome.

• Haemolysis.

• Inconsequential neonatal jaundice.

• Breast-milk jaundice.

• Other causes of hepatic pathology such as hepatitis (but these will usually have deranged LFTs).

Management of Crigler-Najjar syndrome^{1 4}

Currently, liver transplantation is the only available specific treatment.

Type I

• Early treatment of hyperbilirubinaemia is needed to avoid kernicterus:
  

  • Plasmapheresis is the most effective process to remove the excess unconjugated bilirubin from the blood during severe hyperbilirubinaemia crisis.

  • Pharmacological treatments include enzyme-inducing agents (phenobarbital), bilirubin-binding agents (calcium phosphate, orlistat), choleretics (ursodeoxycholic acid), heme-oxygenase inhibitors (Tin-protoporphyrin, Zinc-protoporphyrin).

  • When unconjugated bilirubin reaches toxic levels, the disease is managed with aggressive intravenous fluid hydration, administration of albumin, and possibly plasma exchange to avoid serious neurological consequences.

  • Oral calcium phosphate may also be given to aid bilirubin excretion.

• Liver transplantation:

  • Liver transplantation has achieved good success rates, with better results achieved before the development of any neurological dysfunction.

  • Living-related donor transplantation has been carried out and may reduce the degree of necessary immunosuppression and help overcome the shortage of donor organs.⁸

  • Some advocate the use of transplantation as early as possible to avoid complications.⁹

• Inhibitors of haem oxygenase such as tin-mesoporphyrin are experimental treatments that offer transient reduction in bilirubin levels and may offer hope for ameliorating the condition in the future.

• Gene therapy may offer hope of future cure/therapy when technological expertise improves; there have been promising results in animal models of the disease.^{10 11}

Type II

• Usually no treatment is necessary.

• Phenobarbital can be used if there is persistently high bilirubinaemia.

• Avoid using drugs that displace unconjugated bilirubin from plasma-protein binding sites - eg, sulfonamides, salicylates, penicillin

• During crises of hyperbilirubinaemia, whole-body blue-light phototherapy or plasma exchange transfusion may be utilised to lower bilirubin levels so as to prevent encephalopathy.

Complications of Crigler-Najjar syndrome

Neurological complications due to kernicterus, or intermittent severe hyperbilirubinaemia.

Prognosis^{4 5}

Type I

• This used to have an appalling prognosis, with death by the age of 2 years.

• Since the advent of plasma exchange transfusion, phototherapy and the possibility of hepatic transplantation, the outlook is much better with survival into teens or early adulthood now more usual.

• The efficacy of phototherapy seems to decrease in the teenage years, leading to difficulties in management if hepatic transplantation is not possible.

• Long-term survival after transplantation seems to be fairly good but there have so far been too few cases to reach conclusions about its overall effectiveness.

Type II

• Patients should have a normal or near-normal life expectancy.