Crigler-Najjar Syndrome

Crigler-Najjar syndrome is a rare inherited condition where the liver cannot properly break down bilirubin, a substance produced when red blood cells are broken down. This leads to a dangerous buildup in the body that can cause serious brain damage if not treated promptly.

Table of contents

• What is Crigler-Najjar syndrome?
• Associated anatomy
• Types of Crigler-Najjar syndrome
• How common is this condition?
• Causes and inheritance
• Symptoms and complications
• Diagnosis
• Treatment
• Outlook and life expectancy

What is Crigler-Najjar syndrome?

Crigler-Najjar syndrome is a rare genetic condition that affects how the body processes bilirubin, a yellowish-orange substance created when red blood cells break down at the end of their lifespan^[1]. In healthy people, the liver converts toxic bilirubin into a harmless form that leaves the body through stool^[1].

In people with Crigler-Najjar syndrome, the liver cannot properly break down bilirubin because of a missing or faulty enzyme. As a result, toxic bilirubin builds up in the blood and tissues, causing the skin and whites of the eyes to turn yellow, a condition called jaundice^[3]. Without treatment, this buildup can lead to serious and life-threatening complications^[1].

Familial nonhemolytic unconjugated hyperbilirubinemia, Hereditary unconjugated hyperbilirubinemia, Arias syndrome

Associated anatomy

• Liver
• Brain
• Blood

Types of Crigler-Najjar syndrome

There are two types of Crigler-Najjar syndrome, which differ greatly in how severe they are^[1].

Type 1 (CN1) is the more severe form of the condition. People with type 1 have little to no activity of the enzyme needed to break down bilirubin^[2]. This causes bilirubin levels to rise to very high levels, usually above 20 mg/dL (340 μmol/L), and sometimes as high as 50 mg/dL (850 μmol/L)^[9]. Jaundice appears within the first few days of life and gets worse over time^[3]. Without proper treatment, most children with type 1 do not survive past childhood because of complications from the disease^[1].

Type 2 (CN2), also known as Arias syndrome, is a less severe form. People with type 2 have reduced enzyme activity, usually less than 20 percent of normal levels, but the enzyme is not completely absent^[2]. Bilirubin levels are lower than in type 1, typically between 3.5 and 20 mg/dL (60-340 μmol/L)^[9]. Jaundice may come and go and often worsens during times of stress or illness^[2]. People with type 2 usually have a normal life expectancy with proper management^[1].

How common is this condition?

Crigler-Najjar syndrome is extremely rare and affects fewer than 1 in 1 million newborns worldwide^[1]. Some sources estimate the rate to be between 0.6 and 1 per million live births^[6]. Only about 100 cases have been recorded in medical literature^[17].

Causes and inheritance

Crigler-Najjar syndrome is caused by changes, called mutations, in a gene named UGT1A1^[3]. This gene provides instructions for making an enzyme called bilirubin-UGT (bilirubin uridine diphosphate glucuronosyl transferase), which is found mainly in liver cells^[3].

The enzyme performs a chemical reaction called glucuronidation. During this process, the enzyme attaches a compound called glucuronic acid to bilirubin, converting it from a toxic form to a water-soluble form that can be removed from the body^[3].

When the UGT1A1 gene is mutated, the enzyme either does not work at all or works very poorly. People with type 1 have no enzyme function, while people with type 2 have less than 20 percent of normal function^[3]. This loss of function prevents the body from breaking down bilirubin, causing it to build up to toxic levels^[3].

Crigler-Najjar syndrome is inherited in an autosomal recessive pattern^[1]. This means that a child must receive a mutated copy of the UGT1A1 gene from both parents to develop the condition. Parents who each carry one mutated gene are called carriers and typically do not have symptoms themselves^[1]. If only one parent passes on a mutated gene, the child may develop a milder condition called Gilbert’s syndrome^[1].

Symptoms and complications

The main symptom of Crigler-Najjar syndrome is jaundice, where the skin and the whites of the eyes turn yellow^[1]. In newborns, jaundice is common and usually resolves within the first week of life as the liver develops. However, in children with Crigler-Najjar syndrome, jaundice appears within the first few days after birth and persists beyond the newborn period^[1]. The jaundice gets worse over time in type 1, while in type 2 it may be intermittent^[2].

Kernicterus

The most serious complication of Crigler-Najjar syndrome is kernicterus, a form of brain damage caused by very high levels of bilirubin building up in the brain, nerves, and tissues^[1]. This condition is also called bilirubin encephalopathy and is life-threatening even with treatment^[18].

Early symptoms of kernicterus may appear after one month of life or during early childhood. They can also occur later in life if treatment for Crigler-Najjar syndrome is stopped or interrupted by another illness^[1].

Mild symptoms of kernicterus include^[1]:

• Clumsiness
• Muscle spasms
• Problems with sensory perception
• Trouble with fine motor skills, such as grasping objects or fastening buttons
• Twisting or squirming movements of the body, called choreoathetosis
• Underdeveloped tooth enamel

In infants, early warning signs may include^[18]:

• Poor feeding
• Irritability
• Floppy muscles, like a rag doll
• Extreme tiredness (lethargy)
• A high-pitched cry
• No startle reflex
• Vomiting

People with the most severe forms of type 1 Crigler-Najjar syndrome are at very high risk of developing kernicterus, which can lead to permanent neurological damage including hearing loss, deafness, intellectual disability, and paralysis of eye movements^[6].

Diagnosis

Severe jaundice that appears in the first days of life and does not go away may lead doctors to suspect Crigler-Najjar syndrome^[18].

Tests used to help confirm the diagnosis may include^[18]:

• Physical examination
• Liver blood tests, including a split bilirubin test that measures the amounts of conjugated (processed) and unconjugated (unprocessed) bilirubin in the blood
• Urine test
• Genetic testing to look for mutations in the UGT1A1 gene
• Liver biopsy to examine liver tissue and measure enzyme activity

A drug called phenobarbital can be used to help determine whether a child has type 1 or type 2 Crigler-Najjar syndrome^[18]. Phenobarbital reduces bilirubin levels in people with type 2 but has no effect on those with type 1^[5]. It is very important to identify which type a child has because the treatments and outlook differ significantly^[18].

Treatment

Treatment for Crigler-Najjar syndrome depends on the type and severity of the condition.

Phototherapy

The most common treatment for Crigler-Najjar syndrome, especially type 1, is phototherapy^[6]. During phototherapy, the skin is exposed to special bright blue LED lights, similar to a tanning bed. These lights break down bilirubin in the skin so it is no longer toxic and can be removed from the body^[17].

For children with type 1, phototherapy must be used throughout their entire life, often requiring 10 to 12 hours of treatment every day^[6]. While phototherapy is effective at reducing bilirubin levels in young children, it becomes less effective as children grow older because thickened skin blocks the light^[5]. The need for prolonged daily phototherapy can have a major impact on quality of life^[6].

Medications

For type 2 Crigler-Najjar syndrome, a medication called phenobarbital can help lower bilirubin levels^[2]. Phenobarbital works by increasing the activity of the enzyme that breaks down bilirubin. However, this medication does not work for people with type 1 because they have no enzyme activity^[2].

Other treatments that may be used include calcium compounds to help remove bilirubin in the gut and blood transfusions to help control bilirubin levels^[5].

Liver transplant

A liver transplant is currently the only curative treatment for severe type 1 Crigler-Najjar syndrome^[2]. During a liver transplant, the damaged liver is replaced with a healthy liver from a deceased donor or a piece of healthy liver from a living donor. Because the new liver can properly convert bilirubin and remove it from the body, a transplant can be life-saving^[17].

However, liver transplants have limitations. There is a limited availability of donor livers, which can mean years of waiting. After transplant, patients need to take medications that suppress the immune system for the rest of their lives to prevent rejection of the new liver. These medications can cause unwanted side effects, including increased risk of cancer and viral infections^[6].

Gene therapy

Researchers are developing new treatments for Crigler-Najjar syndrome, including gene therapy. Gene therapy aims to restore the function of the missing enzyme by delivering a working copy of the UGT1A1 gene to the liver^[6]. An international clinical trial for a gene therapy treatment called GNT-0003 is currently underway^[6].

Outlook and life expectancy

The outlook for people with Crigler-Najjar syndrome depends on the type and how well it is managed.

People with type 2 Crigler-Najjar syndrome generally have a good outlook. They typically survive into adulthood without serious neurological problems if the condition is properly managed with medications and monitoring^[1]. They may still experience jaundice, but symptoms are generally milder and less organ damage occurs^[5].

Type 1 Crigler-Najjar syndrome has a more serious outlook. Before the availability of phototherapy and liver transplants, most children with type 1 died in early childhood from brain damage caused by kernicterus^[5]. Today, with proper treatment including daily phototherapy, many children can survive longer. However, phototherapy becomes less effective with age, and without a liver transplant, people with type 1 continue to have jaundice into adulthood and are at constant risk of developing brain damage^[5]. Even with regular treatment, people with type 1 who reach adulthood may develop some degree of brain damage. The life expectancy for someone with type 1 disease who does not receive a liver transplant is estimated to be around 30 years^[5].

A successful liver transplant can dramatically improve the outlook for people with type 1 Crigler-Najjar syndrome, allowing them to live without the need for daily phototherapy and eliminating the risk of kernicterus^[17].