Synonyms: Crigler-Najjar disease, Arias' syndrome (type II 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. This leads to either virtually absent enzyme activity (type I), or impaired activity (type II). It is a rare disease with only hundreds of reported cases worldwide.
The other major unconjugated hyperbilirubinaemia, Gilbert's syndrome, is much more common (estimated 3–7% of the adult population). 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.
- Very rare; only about 100 cases have been reported.
- Autosomal recessive inheritance.
- Severe neonatal jaundice that formerly caused severe kernicterus or brain damage and death within 24 months - can now be ameliorated or treated in many cases.
- Total serum bilirubin high at 342-770 μmol/L (20-45 mg/dL).
- Phenobarbital has no effect on bilirubin levels.
- Absence of bilirubin glucuronides in bile.
Type II (Arias' syndrome)
- More common than type I but still very rare.
- Predominantly autosomal recessive inheritance.
- Total serum bilirubin 103-342 μmol/L (6-20 mg/dL).
- Mild persistent jaundice in childhood, without brain damage.
- Phenobarbital reduces bilirubin levels by ~30%.
- Bilirubin glucuronides present in bile.
- It is extremely rare. True incidence/prevalence are unknown. Only a few hundred cases are reported worldwide.
- Type II appears to be more common than type I 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 institution of international conferences for all interested parties.
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- 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.
- 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.
- 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.
- Phenobarbital response is ~30% reduction in bilirubin level in type II, but no reduction in type I.
Other causes of neonatal jaundice, including:
- Gilbert's syndrome.
- Inconsequential neonatal jaundice.
- Breast-milk jaundice.
- Other causes of hepatic pathology such as hepatitis (but these will usually have deranged LFTs).
- 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.
- 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.
- Some advocate the use of transplantation as early as possible to avoid complications.
- 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.
- 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.
- Type I disease:
- This 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, 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.
Neurological disease due to kernicterus, or intermittent severe hyperbilirubinaemia.
Further reading & references
- Crigler-Najjar syndrome; biographical/historical account of those involved in discovering/studying the syndrome, whonamedit.com
- Crigler-Najjar Syndrome, Type I; Online Mendelian Inheritance in Man (OMIM)
- Crigler-Najjar Syndrome, Type II; Online Mendelian Inheritance in Man (OMIM)
- Roy PK et al; Crigler-Najjar Syndrome, Medscape, Mar 2012
- Lucey JF, Suresh GK, Kappas A; Crigler-Najjar syndrome, 1952-2000: learning from parents and patients about a very rare disease and using the internet to recruit patients for studies. Pediatrics. 2000 May;105(5):1152-3.
- Al Shurafa H, Wali S, Chehab MS, et al; Living-related liver transplantation for Crigler-Najjar syndrome in Saudi Arabia. Clin Transplant. 2002 Jun;16(3):222-6.
- Schauer R, Lang T, Zimmermann A, et al; Successful liver transplantation of two brothers with crigler-najjar syndrome type 1 using a single cadaveric organ. Transplantation. 2002 Jan 15;73(1):67-9.
- van der Wegen P, Louwen R, Imam AM, et al; Successful treatment of UGT1A1 deficiency in a rat model of Crigler-Najjar disease by intravenous administration of a liver-specific lentiviral vector. Mol Ther. 2006 Feb;13(2):374-81. Epub 2005 Dec 5.
- Seppen J, Bakker C, de Jong B, et al; Adeno-associated Virus Vector Serotypes Mediate Sustained Correction of Bilirubin UDP Glucuronosyltransferase Deficiency in Rats.; Mol Ther. 2006 Mar 30;.
|Original Author: Dr Sean Kavanagh||Current Version: Dr Colin Tidy||Peer Reviewer: Dr Adrian Bonsall|
|Last Checked: 04/01/2013||Document ID: 778 Version: 23||© EMIS|
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