Background
Crigler-Najjar syndrome (CNS) is a rare autosomal recessive disorder of bilirubin metabolism. Two distinct forms have been described, as follows: type 1 and type 2. Type 1 Crigler-Najjar syndrome, first described in 1952 by Crigler and Najjar, is associated with neonatal unconjugated hyperbilirubinemia (high levels) and kernicterus. Type 2 Crigler-Najjar syndrome (also called Arias syndrome), first described in 1962 by Arias, presents with a lower serum bilirubin level and responds to phenobarbital treatment.
The differential diagnosis of hyperbilirubinemia can be divided into 3 broad groups: (1) disorders of excessive bilirubin production (eg, hemolysis, ineffective erythropoiesis), (2) impaired hepatic handling of bilirubin (eg, hepatitis, cirrhosis, inherited syndromes), and (3) defective bile outflow (eg, intrahepatic or extrahepatic biliary obstruction).
A markedly elevated unconjugated (indirect) hyperbilirubinemia is observed in inherited disorders such as Gilbert syndrome and Crigler-Najjar syndrome. Among the inherited unconjugated hyperbilirubinemias, Gilbert syndrome is believed to affect approximately 3-7% of the adult population. Crigler-Najjar syndrome is a much rarer disorder, with only a few hundred cases described in the literature.
Pathophysiology
Effective elimination of bilirubin requires its conversion to polar derivatives. In humans, conjugation of bilirubin with the sugar molecule glucuronic acid accomplishes this conversion in a process called glucuronidation.
Crigler-Najjar syndrome is elicited by a lack or deficiency of the enzyme uridine diphosphate glycosyltransferase (UGT). Type 1 Crigler-Najjar syndrome is associated with an almost complete absence of the enzyme, which results in very high levels of unconjugated hyperbilirubinemia (up to 50 mg/dL) at birth. Lower levels of serum bilirubin (up to 20 mg/dL) and markedly depressed activity of hepatic UGT are characteristic of type 2 Crigler-Najjar syndrome (Arias syndrome). Importantly, treatment with phenobarbital can induce the expression of UGT in patients with type 2 Crigler-Najjar syndrome, with a decrease in the serum bilirubin level of approximately 25%.
Crigler-Najjar syndrome is caused by alterations in the coding sequence of UGT. This results in complete absence of UGT or the presence of abnormal UGT with reduced or no enzyme activity. In contrast, in Gilbert syndrome, the defect is in the promoter region of UGT, and reduced amounts of the normal protein are produced.
Epidemiology
Frequency
United States
Crigler-Najjar syndrome is an extremely rare disorder that follows an autosomal recessive pattern of inheritance. Incidence is less than 1 case per 1,000,000 births. Only a few hundred cases have been described in the world literature, and the real prevalence is unknown.
Mortality/Morbidity
If left untreated, type 1 Crigler-Najjar syndrome is uniformly lethal secondary to the development of kernicterus by age 2 years. Although much rarer, bilirubin encephalopathy can also occur in type 2 Crigler-Najjar syndrome, usually when patients experience a superimposed infection or stress.
Race
Crigler-Najjar syndrome is thought to affect all races equally.
Sex
Crigler-Najjar syndrome occurs in both sexes equally.
Age
If left untreated, type 1 Crigler-Najjar syndrome is uniformly lethal secondary to the development of kernicterus by age 2 years. Although much rarer, bilirubin encephalopathy can also occur in type 2 Crigler-Najjar syndrome, usually when patients experience a superimposed infection or stress.
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