Crigler–Najjar syndrome

Overview

Crigler–Najjar syndrome is a rare inherited disorder that affects the metabolism of bilirubin, a substance produced during the normal breakdown of red blood cells. It is characterized by a deficiency or absence of the enzyme uridine diphosphate-glucuronosyltransferase (UGT1A1), which is necessary for converting unconjugated (indirect) bilirubin into a form that can be excreted by the liver. This leads to a buildup of unconjugated bilirubin in the blood, resulting in severe jaundice and a risk of bilirubin-induced neurological damage known as kernicterus.

Causes

Crigler–Najjar syndrome is caused by mutations in the UGT1A1 gene, which encodes the UGT1A1 enzyme. It is inherited in an autosomal recessive pattern, meaning both copies of the gene must be mutated for the condition to manifest. There are two types of the syndrome:

• Type I: Complete absence of UGT1A1 enzyme activity. This form is more severe and usually appears in the first days of life.

• Type II (Arias syndrome): Partial deficiency of the enzyme. It is generally milder and may respond to certain medications.

Symptoms

The symptoms of Crigler–Najjar syndrome vary depending on the type and severity of the enzyme deficiency. Common symptoms include:

• Severe jaundice: Yellowing of the skin and eyes, often appearing shortly after birth

• Unconjugated hyperbilirubinemia: Very high levels of indirect bilirubin in the blood

• Kernicterus: A potentially fatal form of brain damage caused by bilirubin toxicity (more common in Type I)

• Fatigue, poor feeding, and lethargy: In affected infants

• Normal liver function tests: Aside from bilirubin levels, liver enzymes and function may appear normal

In Type II, symptoms are usually milder, and affected individuals may have intermittent jaundice that worsens during illness, fasting, or stress.

Diagnosis

Crigler–Najjar syndrome is diagnosed based on clinical presentation, laboratory testing, and genetic analysis. Diagnostic steps include:

• Serum bilirubin measurement: Elevated levels of unconjugated bilirubin without signs of liver disease

• Liver function tests: Typically normal except for bilirubin

• Response to phenobarbital: Type II patients show a reduction in bilirubin levels, while Type I does not respond

• Genetic testing: To confirm mutations in the UGT1A1 gene and distinguish between Type I and Type II

• Liver biopsy (rare): May be used in complex cases to evaluate UGT1A1 activity

Treatment

Treatment depends on the type and severity of the syndrome:

• Phototherapy: Main treatment for Type I. High-intensity blue light helps convert bilirubin into a water-soluble form that can be excreted

• Plasmapheresis or exchange transfusions: Used in emergencies to quickly reduce bilirubin levels

• Liver transplant: The only curative treatment for Type I; provides the missing enzyme and eliminates the risk of kernicterus

• Phenobarbital: Effective in reducing bilirubin levels in Type II patients by inducing residual UGT1A1 activity

• Avoidance of triggers: Fasting, dehydration, and certain medications that increase bilirubin levels should be avoided

Prognosis

The prognosis for Crigler–Najjar syndrome depends on the type:

• Type I: Without treatment, there is a high risk of kernicterus and early death. With consistent phototherapy and liver transplant, life expectancy can be significantly improved.

• Type II: Generally has a good prognosis, especially with medication and lifestyle management. Severe complications are rare, and life expectancy is usually normal.

Early diagnosis and proactive management are critical to preventing irreversible neurological damage, especially in Type I cases.