Three conditions are distinguished in unconjugated hyperbilirubinemia caused by deficiencies in the conjugating enzyme: Crigler-Najjar syndrome types 1 and 2, and Gilbert's syndrome. The severity of the disease depends on the serum bilirubin level which in Crigler-Najjar syndrome type 2 is intermediate between the often-fatal type 1 disease and the inconsequential Gilbert's syndrome. Patients with the type 2 disease are successfully treated with phenobarbital.
The Crigler-Najjar syndrome is due to increased serum bilirubin, which could be toxic to the central nervous system. Crigler-Najjar syndrome type 2 (also called Arias syndrome) is less severe than the type 1 syndrome.
Bilirubin is a degradation product of heme; most of it is derived from the hemoglobin of old or dysfunctional red cells. Bilirubin is a toxic hydrophobic compound that is bound to serum albumin in the circulation. At very high concentrations, it can pass through the blood-brain barrier and cause kernicterus, a severe, often fatal neurological disease. Serum concentrations of bilirubin rise when its production is increased, or its processing or excretion is reduced. In the liver, bilirubin is converted to a form soluble in water (bilirubin-glucuronide) and then excreted in the bile. The conjugation reaction is catalyzed by bilirubin-uridinediphosphoglucuronate-glucuronosyltransferase (UDP-glucuronosyltransferase or UGT1A1) . All three forms of hyperbilirubinemia - Crigler-Najjar syndrome (CNS) types 1 and 2, and Gilbert's syndrome - can be attributed to deficiencies of the UGT1A1 enzyme. The residual enzyme activity defines the severity of the disease: a near-complete absence of UGT1A1 results in CNS1 syndrome, whereas a decreased activity of the enzyme gives rise to CNS2 disease.
Patients suffering from Crigler-Najjar syndrome present with jaundice, but without hemolysis or other evidence of increased production of bilirubin, and without liver disease. Whereas in CNS1 patients jaundice develops almost immediately after birth and continues to progress, CNS2 patients may not present with any symptoms and are often diagnosed later . Kernicterus presenting with hypotonia, deafness, and lethargy, which very often accompanies the CNS1 syndrome, is only exceptionally observed in the CNS2 syndrome. Symptoms are often aggravated by sickness or fasting, but brain damage can usually be avoided in patients with CNS2. High bilirubin levels can be effectively treated in CNS2 patients with phenobarbital or other inducers of UGT1A1 . Some hormones and antibiotics may inhibit the enzyme's activity.
The Crigler-Najjar syndrome is a very rare disease: only a few hundred cases are known in the world (the benign Gilbert's syndrome occurs widely, in around 5% of the population) . Inheritance of the type 2 disease is somewhat complex: early work reported an autosomal dominant pattern , but other evidence points to autosomal recessive inheritance. One study describes that a healthy child was born to a CNS2 patient who was treated with phenobarbital during pregnancy .
The only physical sign of hyperbilirubinemia is jaundice. Crigler-Najjar syndrome may be suspected in neonates if jaundice lasts longer than usual. Differentiating Crigler-Najjar syndrome from other disease involves exclusion of increased production of bilirubin (for example of hemolysis) and conditions leading to impaired uptake or excretion by the liver. Since the Crigler-Najjar syndromes are due to deficiencies in the conjugating enzyme, elevated levels of unconjugated bilirubin (indirect bilirubin), as opposed to conjugated bilirubin (direct bilirubin), will be detected in both type 1 and type 2 disease.
Type 2 and type 1 versions of Crigler-Najjar syndrome can be distinguished from one another on the basis of several criteria. Serum bilirubin concentrations are usually much higher in type 1 disease (20-50 mg/dL) than in type 2 (7-20 mg/dL). CNS2 patients respond to enzyme induction by phenobarbital, whereas patients with CNS1 - with essentially complete lack of the conjugating enzyme – do not . For the same reason, CNS2 patients, but not CNS1 patients, have bilirubin glucuronides (albeit at reduced concentrations) in their bile.
Definitive diagnosis and distinction between type 1 and type 2 conditions can be reached by examining UGT1A1 activities in liver biopsies, or by identifying the types of deficiency in the UGT1A1 gene. Patients with CNS2 often display homozygous or double heterozygous missense mutations ; or, occasionally, are heterozygous for a nonsense and missense mutation . The presence of a promoter mutation characteristic of Gilbert's syndrome occurring together with a missense mutation can also result in CNS2 . Certain mutations have been shown to be associated with relatively high levels of bilirubin in some populations of CNS2 patients .
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