CRIGLER-NAJJAR
SYNDROME

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Please refer also to the following links:
CriglerNajjar.com Web pages
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Crigler-Najjar.com Web pages (pdf version)
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Definition
Crigler-Najjar syndrome is a genetic disease characterized by a persistent unconjugated hyperbilirubinemia (elevated bilirubin levels).
Bilirubin is the waste product of the breakdown of hemoglobin during the normal turnover of red blood cells. Bilirubin is not soluble in water and before excretion in the bile must be associated with a substance called glucuronid acid. This process takes place in the liver thanks to the bilirubin-uridine diphosphoglucuronate glucuronosyltransferase (B-UDPGT), also known as UDP-glucuronosyltransferase 1A1 (UGT1A1) enzyme. In Crigler-Najjar patients the enzyme is either inactive (type I) or severely reduced (type II). Therefore bilirubin cannot be excreted into the bile and remains in the blood. The high plasma level of unconjugated bilirubin leads to jaundice and may lead to kernicterus (bilirubin encephalopathy) due to bilirubin toxicity.
Clinical Manifestation

Crigler-Najjar syndrome is manifested by severe, persistent jaundice, a condition in which the skin and the whites of the eyes become yellow. This is due to excessive plasmatic levels of bilirubin (> 20 mg/dL in Crigler-Najjar type I patients). Whether untreated severe jaundice may result in brain damage (kernicterus) with possible permanent effects. As results of brain damage clinical manifestations of kernicterus include hypotonia, lethargy, deafness, oculomotor palsy.
Treatment
Current therapy mainly consists of phototherapy (10-12 hours per day) to reduce bilirubin levels, and consequently the risk to develop kernicterus. Patient's survival is dependent on the indefinite continuation of this therapy. Although initially very effective, phototherapy is inconvenient and the efficacy of this treatment is reduced with ageing due to increased thickness of skin and body surface/weight ratio; thus, patients are again at risk for kernicterus around time of puberty.
To improve effectiveness of phototherapy it is best to:
    • Change lamps after about 1,000-1,500 hours of use (approximately every four to six months)
    • Keep the light source close to the body (about 15-20 centimeters, 6-8 inches)
    • Maximize skin exposure to light
    • Use solid white sheets
    • Place reflective surfaces (mirrors and emergency blankets) around the bed

    • (you might find more information in the Phototherapy page)
Liver transplantation is an efficacious therapy but the number of donor organs is limited and it requires life-long immune suppression.
Hepatocyte transplantation (transplantation of hepatic cells, i.e. hepatocytes, rather than whole liver) has been performed on a limited number of patients as an experimental therapeutic procedure (you might find some reports in the news page). Major limitations hampering a more generalized clinical application of this option include the transient benefit in the correction of the disorder, the need of suitable sources for cell isolation and technical problems such as criopreservation of isolated cells.
Other treatments aiming at reducing bilirubin entero-hepatic circulation have been proposed including oral administration of calcium phosphate, cholestyramine and agar. During 2007 results of a clinical trial using oral administration of Orlistat have been published. These data indicated an increased fecal excretion of fat and unconjugated bilirubin with concomitant decreased levels of plasmatic unconjugated bilirubin.
Gene therapy is considered a promising experimental option. During 2017-2018 several clinical trials have been proposed (you might find more information in the clinical trial page)
Genetics
The disease is inherited as an autosomal recessive trait, meaning that the gene involved is not on one of the sex chromosomes; it also means that in order for a person to have the disorder the genetic change must be present in both copies of the gene, one inherited from the mother and one from the father. In other words, parents of a Crigler-Najjar patient have a copy of the UGT1A1 gene mutated (they are "carriers" of the disease). This do not have a significant effect on the bilirubin levels, since one copy of the gene is functional. In Crigler-Najjar patients both of the copies of the gene are mutated. Two carriers have a 25% chance with each pregnancy of having a child affected by the disorder; a 50% chance of having an unaffected child who is a carrier of the disorder and a 25% chance that the child will not have the disorder and will not be a carrier (see also Crigler-Najjar and pregnancy page).
Several gene alterations have been discovered in Crigler-Najjar syndrome patients, leading to reduced or absent UGT1A1 activity causing hyperbilirubinemia. Full-length cDNA for human UGT1A1 has been cloned and sequenced.
Crigler-Najjar syndrome is very rare, real incidence is unknown (approx. less than 1 case per 1,000,000 births).



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