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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 glucuronosyltransferase (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 I) or impaired activity (type II). It is a rare disease with only hundreds of reported cases worldwide.
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.
Crigler-Najjar syndrome involves two very rare (less than 1/106 live births) autosomal recessive disorders (types I and II), which differ in the degree of UGT1A1 deficit and consequently in the clinical presentation.
- 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%.
- 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.
- 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:
- 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.[9, 10]
- 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.
Neurological complications due to kernicterus, or intermittent severe hyperbilirubinaemia.
- 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.
- Patients should have a normal or near-normal life expectancy.
Further reading and 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)
Memon N, Weinberger BI, Hegyi T, et al; Inherited disorders of bilirubin clearance. Pediatr Res. 2016 Mar79(3):378-86. doi: 10.1038/pr.2015.247. Epub 2015 Nov 23.
Sticova E, Jirsa M; New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol. 2013 Oct 1419(38):6398-6407.
Radlovic N; Hereditary hyperbilirubinemias. Srp Arh Celok Lek. 2014 Mar-Apr142(3-4):257-60.
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 May105(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 Jun16(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 1573(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 Feb13(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.