Crigler-Najjar syndrome (CNS) is a very rare genetic disorder that affects the liver. In this condition, your body is unable to convert a product known as unconjugated bilirubin to conjugated bilirubin. Unconjugated bilirubin cannot be excreted from the body and hence, it accumulates and causes the symptoms associated with this disease. There are two main types of this disease; CNI and CNII.

The first cases of CNS were discovered quite a while ago, in 1952 by two doctors called Dr Crigler and Dr Najjar. As a genetic disorder, it can occur in anyone who inherits the faulty gene from their parents and it is usually discovered soon after birth or during childhood. 

Pathophysiology 

When the red blood cells in our bodies are broken down, one of the by-products formed is known as bilirubin and it is formed in its unconjugated form. This unconjugated form is fat-soluble so it cannot be dissolved in water and excreted from the body. For the body to be able to excrete it, unconjugated bilirubin is transported to the liver where a particular enzyme known as UDP-glucuronosyltransferase (UGT) converts this unconjugated form to conjugated bilirubin. The conjugated version of bilirubin is water-soluble and is then easily excreted from the body.¹

In CNS, the body has little or no amounts of the UGT enzyme and thus the bilirubin cannot be converted to its conjugated form. The unconjugated bilirubin cannot be dissolved in water and excreted so it accumulates in the body and deposits in various organs such as the skin and brain. Unconjugated bilirubin can easily cross the blood-brain barrier and deposit in the brain, causing neurological symptoms. Some very tiny amounts of unconjugated bilirubin can still be removed from the body through the bile and small intestine but this is nowhere near enough to correct the disorder. 

There are two types of CNS, CNI and CNII. In CNI, there is a complete lack of the enzyme UGT and it is a very dangerous and life-threatening version of the disease. In CNII, there are a few amounts of UGT which are present, which are lower than normal but it makes the disease less severe and the symptoms more mild. 

Clinical manifestations

The severity of the symptoms of CNS depends on the type of disease present. The main clinical sign is persistent jaundice. Jaundice is the yellowing of the skin and/or eyes and it is caused due to increased amounts of unconjugated bilirubin in the blood. All newborns experience jaundice but the jaundice associated with CNS is resistant and does not go away on its own. 

Besides jaundice, an increased amount of unconjugated bilirubin in the blood can also cause neurological symptoms because of its deposition in the brain.² This condition is called kernicterus and the symptoms in babies might include: 

• Excessive sleepiness
• Poor feeding 
• High pitched crying
• Poor muscle tone (hypotonia)— the baby might appear floppy like a rag-doll
• No startle reflex

In mild versions of the disease, symptoms can be observed in slightly older children who have yet remained undiagnosed and these can include: 

• Clumsiness
• Trouble with fine motor skills 
• The enamel of the teeth might be underdeveloped
• Poor sensory perception 
• Rapid or slow twisting or squirming motion of the body (choreoathetosis)
• Memory problems and hearing problems
• Extreme fatigue/ lethargy

At times, children may present with the acute form of the disease due to an increase in unconjugated bilirubin. When the following symptoms arise, this is a medical emergency and requires urgent medical attention. The symptoms can be: 

• Vomiting
• Diarrhea
• Fever 
• Slurred speech
• Confusion 
• Staggering and falling
• Difficulty swallowing 
• Seizures 

Diagnosis

CNS is first suspected in newborns with persistent jaundice, severe jaundice or jaundice which has a very rapid onset. After a physical examination, during which your doctor will examine the yellowing of the skin and eyes, they will order some further tests. These might include: 

• A full blood count
• Blood tests or stool tests to determine the amount of unconjugated bilirubin accumulated in the body. In CNI, the unconjugated bilirubin levels¹ vary between 20-25 mg/dL but can even go up to 50 mg/dL in severe cases. Since CNII is less severe, the levels usually remain below 20 mg/dL
• In another more definitive test, bile is collected from an upper part of the intestine known as the duodenum, via endoscopy. This bile is then tested for unconjugated bilirubin and there would be significant amounts present in CNI and small amounts present in CNII
• Liver function tests
• Liver biopsy to test for UGT levels 
• Genetic analysis of DNA to check for the presence of the mutated gene 
• Prenatal diagnosis, which is diagnosing your baby before it's even born, is also possible through procedures such as chorionic villus samples or amniotic cells aspiration³

Management and treatment 

The main aim in the management of CNS, is lowering the levels of unconjugated bilirubin in the blood and preventing it from causing permanent neurological damage. The type of treatment needed would depend on the type of CNS and the levels of bilirubin in the blood. 

Phenobarbital: This drug can be taken to manage excessive levels of unconjugated bilirubin but it is mostly used in mild cases of CNII.

Phototherapy: This method uses light waves to remove the excess bilirubin from the body.⁴ Intensive sessions of phototherapy are preferred, especially for CNI, because it is more effective, provides a more rapid response and requires shorter durations of phototherapy sessions. It is a relatively safe method and it is more effective in newborn babies than slightly older children because of their thinner, less pigmented skin. This can allow the light waves to penetrate deeper and clear the excess bilirubin. 

Plasmapheresis: This is a process where a machine is used to separate plasma from blood and then this blood is infused with donor plasma and is returned to the person undergoing the procedure.⁵ It helps in severe cases of high unconjugated bilirubin levels to remove the excess amounts from the blood. 

Liver transplant: This is a surgery in which the damaged liver is replaced by a healthy donor one. It is a good option for CNI and severe cases and it is usually done as early as possible to prevent brain damage.

Research and future direction 

There are several newer treatments which are also being used for the treatment of CNS. One of these new methods is called hepatocyte transplantation (hepatocytes are the cells that make up the liver tissue) and it is a good alternative to liver transplantation. In this procedure, normal hepatocytes are infused into the liver via the hepatic portal vein. It is an effective but temporary procedure which can reduce the levels of unconjugated bilirubin by almost 50%.⁶

Another relatively new method to treat CNS is gene therapy.⁷ In this method, a normal gene which can produce normal amounts of the hormone UGT is introduced via a vector (vehicles used to deliver the healthy gene to the liver). The most commonly used and most effective vector is adenovirus. It can produce a significant decrease in the levels of unconjugated bilirubin without any serious side effects. 

Prognosis 

Unfortunately, you cannot prevent yourself from getting CNS because it is a genetic disorder. However, you can assess the risk involved in passing it on to your children via genetic testing before planning on conceiving. 

CNII has a relatively good prognosis; if it is caught and treated as early as possible, the child can go on to lead a normal and healthy life. However, severe cases of CNI have a poor prognosis, if not treated immediately upon diagnosis. Despite early treatment, most severe cases of CNI will require lifelong treatment for survival. 

Summary

Crigler-Najjar syndrome (CNS) is a rare genetic condition which alters the liver's ability to excrete bilirubin. In a normal body, when red blood cells are broken down, a by-product known as unconjugated bilirubin is converted in the liver by UGT to conjugated bilirubin which is soluble in water. This water solubility allows it to be easily excreted in urine.

In CNS, there is a decrease or lack of the enzyme UGT and thus unconjugated bilirubin accumulates in the body and causes symptoms. It can even cross the blood-brain barrier and produce neurological defects. Symptoms might be noticed soon after birth or later in childhood. The initial symptom noticed might be an extended or severe period of jaundice and in childhood, poor physical and mental development might be the initial indicator. 

Several tests might be conducted to test for CNS but the definitive test consists of collecting bile and testing it for the presence of bilirubin. Once a diagnosis has been reached, prompt treatments need to be done in order to prevent lasting damage. 

There are several treatments available to treat CNS and the type of treatment largely depends on the severity of the disease. There are also several emerging treatments that are being used and tested. More research and clinical trials are needed in order to further the cause in the treatment of this rare genetic condition.