Synonyms: Crigler-Najjar disease, Arias' syndrome (type 2 Crigler-Najjar syndrome)

Crigler-Najjar Syndrome comprises two distinct syndromes of congenital unconjugated hyperbilirubinaemia, due to an inborn error of bilirubin metabolism. There is deficient activity of the enzyme uridine-diphosphate glycosyltransferase (UGT), resulting in an impairment of the ability to conjugate and excrete bilirubin. There are mutations in the structure of the gene, whose locus is on the long arm of chromosome 2.^1,2 This leads to either virtually absent enzyme activity (type 1), or impaired activity (type 2). It is a rare disease with only hundreds of reported cases worldwide.

The other major unconjugated hyperbilirubinaemia, Gilbert's syndrome, is much commoner (estimated 3–7% of adult population).³ It manifests as intermittent bouts of mild to moderate jaundice brought on by drugs and illness, and is due to mutations in the promoter region of the UGT gene.

Epidemiology

• Extremely rare. True incidence/prevalence unknown.⁴ Only a few hundred cases reported worldwide.⁴
• Type 2 appears to be commoner than type 1 but it is still an unusual sporadic disease.
• 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 recent institution of international conferences for all interested parties.⁴

Presentation

Type 1

• If untreated it causes death due to the kernicterus by the age of 2.
• Presents with persistent, marked jaundice at or soon after birth.
• Kernicterus may manifest as hypotonia, deafness, occulomotor palsies and ultimately death.

Type 2

• 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

• 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 1, milder elevation in type 2 at 100-375 μmol/l (6-22 mg/dL).³
• Type 2 cases may show higher, more toxic levels of bilirubin during episodes of haemolysis, intercurrent illness or drug reactions.
• Liver function tests are usually otherwise normal.
• Phenobarbital response is ~30% reduction in bilirubin level in type 2, but no reduction in type 1.

Differential diagnosis

• Gilbert's syndrome.
• Haemolysis.
• Inconsequential neonatal jaundice.
• Breast-milk jaundice.
• Other causes of hepatic pathology such as hepatitis (but these will usually have deranged liver function tests).

Management

Type 1

• Early treatment of hyperbilirubinaemia is needed to avoid kernicterus.
• Initial emergency management may involve plasma exchange transfusion.
• Long-term, whole-body blue-light phototherapy is used to break down bilirubin to more soluble and easily excreted by-products.
• Oral calcium phosphate may also be given to aid bilirubin excretion.
• In the end, most patients will need orthotopic hepatic transplantation which does offer a 'cure', but leaves the problem of rejection and immunosuppressant drug toxicity.
• Living-related donor transplantation has been carried out and may reduce the degree of necessary immunosuppression and help overcome the shortage of donor organs.⁵
• Some advocate the use of transplantation as early as possible to avoid complications.⁶
• 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.^7,8

Type 2

• Usually no treatment is necessary.
• Phenobarbital can be used if persistently high bilirubinaemia.
• Avoid using drugs that displace unconjugated bilirubin from plasma-protein binding-sites, e.g. sulphonamides, 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.

Prognosis

• Type 1 disease:
  • Used to have an appalling prognosis, with death by age 2.
  • Since the advent of plasma exchange transfusion, phototherapy and the possibility of hepatic transplantation, 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 2 patients should have a normal or near-normal life expectancy.

Complications

Neurological disease due to kernicterus, or intermittent severe hyperbilirubinaemia.