Crigler–Najjar syndrome

Crigler–Najjar syndrome or CNS is a rare disorder affecting the metabolism of bilirubin, a chemical formed from the breakdown of red blood cells. The disorder results in an inherited form of non-hemolytic jaundice, which results in high levels of unconjugated bilirubin and often leads to brain damage in infants.

This syndrome is divided into type I and type 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 hundred cases of CNS are known.

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 (310–755) (whereas the reference range for total bilirubin is 2–14 μmol/L).

No UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) expression can be detected in the hepatic 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.

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
 * 12h/d 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 (100–430; thus, there is overlap), 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.

Differential diagnosis
Neonatal jaundice may develop in the presence of sepsis, hypoxia, hypoglycemia, hypothyroidism, hypertrophic pyloric stenosis, galactosemia, fructosemia, and so on.

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, too. There is no evidence for hemolysis. Drug-induced case 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.

Research
One 10-year-old girl with Crigler–Najjar syndrome type I was successfully treated by hepatocyte transplantation.

The homozygous Gunn rat, which lacks the enzyme uridine diphosphate glucuronyltransferase (UDPGT), is an animal model for the study of Crigler–Najjar syndrome. Since there is only one enzyme working improperly, gene therapy for Crigler Najjar is a theoretical option which is being investigated.

Gunn Rat: Dr. C. H. Gunn discovered a mutant rat in 1934 at the Connaught Laboratory in Toronto, Canada. These rats were jaundiced and the defect was transmitted as an autosomal recessive characteristic. Dr Gunn, a Geneticist, bred them at Connaught and later moved to Summerside, Prince Edward Island, Canada to head up the Canadian Experimental Fox Ranch. Gunn rats are still commercially available today from Harlan, Indianapolis, Indiana. Gunn rats are also available from Japan SLC Inc.. This animal model has been extremely valuable for the development of experimental treatments for this disease.

Eponym
The condition is named for John Fielding Crigler (b. 1919), an American Pediatrician and Victor Assad Najjar (b. 1914), a Lebanese-American Pediatrician.