Abnormality in Crigler Najjar syndrome:

Ref: Nelson's Textbook of Pediatrics 18th edition: page no. 1666-67Explanation:Bilirubin is the metabolic end product of heme.Before excretion into bile, it is conjugated with glucuronide by the enzyme bilirubin uridine-di- phosphor-slucuronate glucuronosvl transferase (UDPGT).UDPGT activity is deficient in Crigler- Najjar(CN) syndromes type I and II .Complete absence of UGTIAi activity causes CN type 1.CN type II is due to decreased/ partial deficiency of UGTIAI activity.Crigler-Najjar Syndrome Type I (Glucuronyl Transferase Deficiency )Autosomal recessive traitMutations that cause a premature stop anion or frameshift mutation and thereby abolish UGT1A1 activity.Clinical ManifestationsSevere unconjugated hyperbilirubinemia in the 1st 3 days of lifeKernicterus (Universal complication)Stools are pale yellow.Persistence of unconjugated hyperbilirubinemia at levels >20 mg/dL after the 1st wk of life in the absence of hemolysisDiagnosisEarly age of onset and the extreme level of bilirubin elevation in the absence of hemolysis.Biliary bilirubin concentration is <10 mg/dL (normal concentrations of 50-100 mg/dL)There is no bilirubin glucuronide.Definitive diagnosis - Measuring hepatic glucuronyl transferase activity in a liver biopsyTreatmentRepeated exchange transfusions and phototherapy.Phenobarbital therapy should be considered to determine responsiveness and differentiation between type I and IIPhototherapy is generally continued through the early years of life.In older infants and children, phototherapy is used mainly during sleep so as not to interfere with normal activities.Adjuvant therapy using agents that bind photobilirubin products such as calcium phosphate, cholestyramine, or agar can he used to interfere with the enterohepatic recirculation of bilirubin.Orthotopic liver transplantation cures the diseaseOther therapeutic modalities have included plasmapheresis and limitation of bilirubin production.Inhibiting bilirubin generation, is possible via inhibition of heme oxygenase using meta- lloporphyrin therapy.Crigler-Najjar Syndrome Type II (Partial Glucuronyl Transferase Deficiency)Autosomal recessive disease:It is caused by homozygous missense mutations in UGT1A1. resulting in reduced (partial) enzymatic activity.Type II disease can be distinguished from type I by the marked decline in serum bilirubin level that occurs in type II disease after treatment with phenobarbital secondary to an inducible phenobarbital response element on the UGT1A1 promoter.Clinical ManifestationsWhen this disorder appears in the neonatal period, unconjugated hyperbilirubinemia usually occurs in the 1st 3 days of life;Serum bilirubin concentrations can be in a range compatible with physiologic jaundice or can be at pathologic levels.The concentrations characteristically remain elevated into and after the 3rd wk of life, persisting in a range of 1.5-22 mg/dL;Development of kernicterus is unusual.Stool color is normalThere is no evidence of hemolysis.DiagnosisConcentration of bilirubin in bile is nearly normal in CN type II.Jaundiced infants and young children with type II syndrome respond readily to 5 mg/kg/24 hr of oral phenobarbital, with a decrease in serum bilirubin concentration to 2-3 mg/dL in 7-10 days.TreatmentContinued administration of phenobarbital at 5 mg/kg/24 hr - Achieves long term control of serum bilirubin levels.Orlistat, an irreversible inhibitor of intestinal lipase, induces a mild decrease in plasma bilirubin levels (-10%) in patients with CN I and II.