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home - Liver - Bilirubin Metabolism - Crigler Najjar Syndrome Written by Dr Sebastian Zeki

Crigler Najjar Syndrome

Written by Dr Sebastian Zeki Dec. absorption of bilirubin/ production of bilirubin or inc. clearance Hepatocyte transplantation Diagnosis — Treatment — Distinction of type 1 from type II disease.Type 1 is assoc. with lower [serum bilirubin] -values can overlap with type I, especially with underlying haemolysis.Phenobarbital can reduce type II; not type I.No conjugated bilirubin in type 1.DNA extracted from any tissue can make the diagnosis. Gene therapy —By introduction of a normal bilirubin-UGT gene (UGT1A1).Ex vivo gene transduction — Harvest hepatocytes from patient, culture and insert normal gene. DifficultVector-mediated gene delivery.------Adenoviral vectors — Locate to liver, transfer trangene to non-dividing cells. But need repeated injections which induce immune response.------SV40 and lentiviruses — Less immunogenicity appears to be negligible, dont localise to liver unless given via portal veinReceptor-mediated gene delivery to the liver —Using carrier proteins- short livedSite-directed gene conversion — By aligning specific sequences with a mismatch so host gene repair mechanism used. Calcium phosphate supplementation —Traps unconjugated bilirubin in gut, lowers the [bilirubin] by 20-50 %.Orlistat —Captures intestinal unconjugated bilirubin.Inhibition of bilirubin production —Heme oxygenase, eg tin-protoporphyrin or tin-mesoporphyrin, inhibits enzyme- better in neonates than adults in which the effect is short lived.Plasmapheresis —Most efficient way to deal with a crisis Liver transplantation This has resulted in long-term survival and is the only curative therapy. Phototherapy —Most patients treated with this can survive past puberty, but get kernicterus later. No treatment: Most dead in 18mWith treatment25% brain damage Isolated unconjugated hyper-bilirubin few days after birth Type 1 DiseaseThis is due to mutations in UGT1A1 gene.Because Gilbert’s is so common, patients can have Gilbert’s with Crigler- Najaar which can lead to severe hyperbilirubinemia, since the activity of the normal allele is reduced to about 30 % of normal.Gilbert’s with Crigler-Najaar explains the frequent finding of intermediate levels of hyperbili-rubinemia in the family members of patients with Crigler-Najjar syndrome, both types I and II. Type 2 DiseaseThis is less marked (serum bilirubin <20 mg/dL).50% are icteric at <1 year.Bilirubin ranges from 8-18 mg/dL.UGT defect is much less severe than in type I disease (residual bilirubin-UGT activity of 2-8 % vs up to 38%).The enzyme is catalytically effective only if hyperbilirubinemia is present (low affinity).Only 50 % of bilirubin is conjugated and excreted into bile.Conjugate is mainly bilirubin monoglucu-roniderather than diglucuronide.The molecular defect is in one of 5 exons coding bilirubin-UGT.Unconjugated hyperbilirubinemia is < 20 mg/dL but can rise to 40 mg/dL if fasting/ intercurrent illness.Other LFT’s normal.Only treat high bilirubin if affects QOL -less likely to get neuro problems.Treat with phenobarbital or clofibrate which reduces serum bilirubin levels by >25 %.Patients respond in 2-3 weeks. Crigler-Najjar syndrome

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