Crigler-Najjar Syndrome

What happens in Crigler-Najjar syndrome

When red blood cells reach the end of their life, they are broken down and their hemoglobin becomes unconjugated bilirubin. This form does not dissolve in water. In the liver, the enzyme UGT1A1 attaches a sugar molecule to it ("conjugation"), making it water-soluble so it can leave the body in bile.

In Crigler-Najjar syndrome, changes in the UGT1A1 gene reduce or eliminate this enzyme. Unconjugated bilirubin builds up in the blood. Because it dissolves in fat, it can cross into the brain and damage it, a condition called kernicterus.

The condition is inherited in an autosomal recessive pattern: a child must receive a faulty gene from each parent. Parents are usually healthy carriers. It is more common in communities where parents are more often related.

Types of Crigler-Najjar syndrome

Gilbert syndrome is a much more common and harmless condition affecting the same enzyme, with only mild, intermittent jaundice.

Symptoms

• jaundice: yellowing of the skin and whites of the eyes, persistent from the first days of life in type 1
• in type 2, jaundice may fluctuate and worsen with illness, fasting or stress
• urine and stool color are normal, unlike jaundice from bile duct blockage, because the bilirubin is unconjugated

Signs of bilirubin brain toxicity

• poor feeding, sleepiness and floppiness in babies
• a high-pitched cry, arching of the neck and back, fever
• later: hearing loss, uncontrolled movements, problems with eye movements, intellectual disability

In type 1, the risk of kernicterus continues beyond infancy. Phototherapy becomes less effective with age as the skin thickens, so teenagers and adults remain at risk.

Diagnosis

1. Blood tests: very high unconjugated (indirect) bilirubin with normal liver enzymes and no signs of red cell breakdown (hemolytic anemia).
2. Phenobarbital trial: a fall in bilirubin suggests type 2.
3. Genetic testing of the UGT1A1 gene confirms the diagnosis and type.
4. Bile analysis or liver biopsy is rarely needed now.

Doctors also rule out more common causes of newborn jaundice, such as breastfeeding jaundice, blood group incompatibility and biliary atresia.

Treatment

Type 1

• Phototherapy: blue light converts bilirubin in the skin into forms that can be excreted. Type 1 often requires 10 to 12 hours or more every day, usually overnight, for life until transplant.
• Exchange transfusion and plasmapheresis for dangerously high levels.
• Bilirubin-binding agents such as calcium phosphate or orlistat are used in some centers to reduce reabsorption from the gut, with limited evidence.
• Liver transplant: the only established cure. It provides working enzyme, and is often recommended before brain damage occurs.
• Hepatocyte transplantation and gene therapy are under study in clinical trials.

Type 2

• Phenobarbital increases production of the remaining enzyme and lowers bilirubin. Many people need it long-term or during illnesses.
• Phototherapy during flares.

Avoiding triggers

• avoid prolonged fasting and treat infections promptly
• check all new medicines: some drugs displace bilirubin from albumin in the blood (for example, ceftriaxone in newborns, some sulfonamides) or are processed by the same enzyme

Outlook

With dedicated phototherapy and timely liver transplant, many people with type 1 now reach adulthood without brain damage. Type 2 usually has a good outlook with phenobarbital and avoidance of triggers. Genetic counseling is recommended for families.

Frequently asked questions

What is Crigler-Najjar syndrome?

It is a rare inherited disorder in which the liver lacks enough of the enzyme UGT1A1 to process bilirubin. Unconjugated bilirubin builds up in the blood, causing lifelong jaundice and, in severe cases, risk of brain damage.

What is the difference between Crigler-Najjar type 1 and type 2?

Type 1 has no working enzyme, very high bilirubin from birth, a high risk of brain damage and needs daily phototherapy and usually a liver transplant. Type 2 has some enzyme activity, lower bilirubin, and usually responds to phenobarbital.

How is Crigler-Najjar syndrome treated?

Type 1 is treated with many hours of phototherapy every day and often a liver transplant. Type 2 is usually treated with phenobarbital. Avoiding fasting and certain medicines and treating illnesses quickly help prevent dangerous rises in bilirubin.

Is Crigler-Najjar syndrome the same as Gilbert syndrome?

No. Both involve the same enzyme, but Gilbert syndrome is common and harmless, with only mild, occasional jaundice. Crigler-Najjar syndrome is rare and causes much higher bilirubin levels that can damage the brain.