Crigler–Najjar syndrome

Type I

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,^[1] 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.

Before the availability of phototherapy, these children died of kernicterus (bilirubin encephalopathy) or survived until early adulthood with clear neurological impairment. Today, therapy includes

• 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

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 dominant.^[2]

Differential diagnosis

Neonatal jaundice may develop in the presence of sepsis, hypoxia, hypoglycemia, hypothyroidism, hypertrophic pyloric stenosis, galactosemia, fructosemia, etc.

Hyperbilirubinemia of the unconjugated type may be caused by:

• increased production
  • hemolysis (e.g., hemolytic disease of the newborn, hereditary spherocytosis, sickle cell disease)
  • ineffective erythropoiesis
  • massive tissue necrosis or large hematomas
• decreased clearance
  • drug-induced
  • physiological neonatal jaundice and prematurity
  • liver diseases such as advanced hepatitis or cirrhosis
  • breast milk jaundice and Lucey–Driscoll syndrome
  • Crigler–Najjar syndrome and Gilbert syndrome

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.