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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.
History
Because of its autosomal recessive transmission, consanguinity is a risk factor for Crigler-Najjar
syndrome, especially type 1 Crigler-Najjar syndrome.
Physical
Persistent jaundice is present at or soon after birth in type 1 Crigler-Najjar syndrome. Jaundice may
not manifest until later in infancy or childhood in type 2 Crigler-Najjar syndrome. Kernicterus is the
most worrisome consequence of hyperbilirubinemia and occurs in virtually all patients with untreated
type 1 Crigler-Najjar syndrome, especially in the first few days of life. Bilirubin encephalopathy is rare
in patients with type 2 Crigler-Najjar syndrome, but it can be induced by factors such as infection,
anesthesia, or drug use. Clinical manifestations of kernicterus are hypotonia, deafness, oculomotor
palsy, lethargy, and, ultimately, death.
Causes
Both type 1 and type 2 Crigler-Najjar syndrome are transmitted by autosomal recessive inheritance.
Alterations in the coding sequence of the UGT1 gene result in absent or reduced UGT activity, with
marked impairment of bilirubin conjugation. The UGT1 gene is located on 2q37. Several isoforms
of UGT1 enzyme exist based on the variability in the amino-terminal region of the final protein. These
differences are the result of alternative splicing among 10 (possibly more) different types of exon 1 at
the 5' end of the UGT1 gene and constant exons 2-5 at the 3' end. Thus, the different UGT1 isoforms
are distinguished according to the type of exon 1 they contain.
A report from the The Netherlands by Sneitz et al identified 4 novel UGT1A1 alleles.
[1]
The
investigators noted the presence of 2 mutations in several unrelated patients; they believe this finding
suggests 2 founder effects in The Netherlands. The study also demonstrated a link between 3
structural mutations and the UGT1A1 *28 promoter polymorphism (rs5719145insTA).
[1]

In examining the functional activity of 10 missense mutants (3 that previously reported; 7 that were
found in this study) and assessing their activity toward bilirubin and 8 other UGT1A1 substrates, it
was revealed that 5 mutants had residual activity that varied, depending on the substrate, from
nondetectable to 94% of wild-type UGT1A2 activity.
[1]

Laboratory Studies
Unconjugated hyperbilirubinemia in the presence of normal liver function test findings is characteristic
of Crigler-Najjar syndrome. The usual bilirubin level is 17-50 mg/dL in type 1 Crigler-Najjar syndrome
and 6-22 mg/dL in type 2. Higher bilirubin levels may be seen in type 2 Crigler-Najjar syndrome if
coexisting hemolysis or intercurrent illness is present.
Transferase activity measurements and the response to phenobarbital treatment distinguish type 1
Crigler-Najjar syndrome from type 2. Phenobarbital has no effect in type 1 Crigler-Najjar syndrome
but causes an approximately 25% reduction in plasma bilirubin level in most patients with type 2
Crigler-Najjar syndrome.
Imaging Studies
Findings on abdominal imaging studies, such as plain radiography, CT scanning, or ultrasonography,
are normal in Crigler-Najjar syndrome.
Histologic Findings
Liver histology findings are normal in Crigler-Najjar syndrome.
Medical Care
Patients with type 2 Crigler-Najjar syndrome may not require any treatment or can be managed with
phenobarbital. By contrast, prompt treatment of kernicterus is required in patients with type 1 Crigler-
Najjar syndrome to avoid the potentially devastating neurologicic sequelae.
Emergent management of bilirubin encephalopathy involves plasma exchange transfusion, which acts
by removing the bilirubin-saturated albumin and provides free protein, which draws bilirubin from the
tissues.
Plasma exchange should be accompanied by long-term phototherapy, which helps in the conversion
of bilirubin to more soluble isoforms that can be excreted in the urine. Oral calcium phosphate may be
a useful adjuvant to phototherapy in type 1 Crigler-Najjar syndrome.
Therapies based on gene and cell transfer techniques, although largely experimental at the present
time, are likely to play an important role in the management of Crigler-Najjar syndrome in the future.
[2,
3]

Inhibitors of heme oxygenase, such as tin protoporphyrin or tin-mesoporphyrin, may be helpful in
reducing bilirubin levels emergently, but the effect is short-lived.
Surgical Care
Liver transplantation has been attempted in select patients with type 1 Crigler-Najjar syndrome and
has achieved good success rates, with better results achieved before the development of neurologic
dysfunction.
[4, 5]