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Crigler–Najjar syndrome or CNS is a rare inherited disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of the heme in red blood cells. The disorder results in a form of nonhemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants. The disorder is inherited in an autosomal recessive manner.
This syndrome is divided into types I and II, with the latter sometimes called Arias syndrome. These two types, along with Gilbert's syndrome, Dubin–Johnson syndrome, and Rotor syndrome, make up the five known hereditary defects in bilirubin metabolism. Unlike Gilbert's syndrome, only a few cases of CNS are known.
It is caused by abnormalities in the gene coding for uridine diphosphogluconurate glucuronosyltransferase (UGT1A1). UGT1A1 normally catalyzes the conjugation of bilirubin and glucuronic acid within hepatocytes. Conjugated bilirubin is more water soluble and is excreted in bile.
This is a very rare disease (estimated at 0.6–1.0 per million live births), and consanguinity increases the risk of this condition (other rare diseases may be present). Inheritance is autosomal recessive.
Intense jaundice appears in the first days of life and persists thereafter. Type 1 is characterised by a serum bilirubin usually above 345 µmol/L [20 mg/dL] (range 310–755 µmol/L [18–44 mg/dL]) (whereas the reference range for total bilirubin is 2–14 μmol/L [0.1-0.8 mg/dL]).
No UDP glucuronosyltransferase 1-A1 expression can be detected in the liver tissue. Hence, there is no response to treatment with phenobarbital, which causes CYP450 enzyme induction. Most patients (type IA) have a mutation in one of the common exons (2 to 5), and have difficulties conjugating several additional substrates (several drugs and xenobiotics). A smaller percentage of patients (type IB) have mutations limited to the bilirubin-specific A1 exon; their conjugation defect is mostly restricted to bilirubin itself.
- exchange transfusions in the immediate neonatal period
- 12 hours/day phototherapy
- heme oxygenase inhibitors to reduce transient worsening of hyperbilirubinemia (although the effect decreases over time)
- oral calcium phosphate and carbonate to form complexes with bilirubin in the gut
- liver transplantation before the onset of brain damage and before phototherapy becomes ineffective at later age
Type II differs from type I in several aspects:
- Bilirubin levels are generally below 345 µmol/L [20 mg/dL] (range 100–430 µmol/L [6–24 mg/dL]; thus, overlap occurs), and some cases are only detected later in life.
- Because of lower serum bilirubin, kernicterus is rare in type II.
- Bile is pigmented, instead of pale in type I or dark as normal, and monoconjugates constitute the largest fraction of bile conjugates.
- UGT1A1 is present at reduced but detectable levels (typically <10% of normal), because of single base pair mutations.
- Therefore, treatment with phenobarbital is effective, generally with a decrease of at least 25% in serum bilirubin. In fact, this can be used, along with these other factors, to differentiate type I and II.
- The inheritance pattern of Crigler–Najjar syndrome type II has been difficult to determine, but is generally considered to be autosomal recessive.
Hyperbilirubinemia of the unconjugated type may be caused by:
- increased production
- decreased clearance
In Crigler–Najjar syndrome and Gilbert syndrome, routine liver function tests are normal, and hepatic histology usually is normal, too. No evidence for hemolysis is seen. Drug-induced cases typically regress after discontinuation of the substance. Physiological neonatal jaundice may peak at 85–170 µmol/l and decline to normal adult concentrations within two weeks. Prematurity results in higher levels.
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The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since only one enzyme is working improperly, gene therapy for Crigler-Najjar is a theoretical option which is being investigated.
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