Crigler-Najjar syndrome: causes, types, treatment and outlook

Bilirubin is a yellow waste product made when red blood cells are broken down. The NHS explains that the liver normally removes it from the body. In Crigler-Najjar syndrome an inherited fault in the gene for an enzyme called UGT1A1 means the liver cannot make bilirubin water-soluble so that it can be passed out in bile. Unconjugated (indirect) bilirubin therefore accumulates, causing jaundice, a yellow tint to the skin and the whites of the eyes.

It is inherited in an autosomal recessive pattern, meaning a child is affected when they inherit a faulty copy of the gene from each parent. According to the Patient.info professional article, the condition affects around 0.6 to 1 in 1 million newborns worldwide, and the true incidence is not known.

It is different from Gilbert's syndrome, which the NHS describes as a common and usually harmless condition that causes episodes of jaundice, and from the very common jaundice of newborn babies, which usually gets better without treatment.

In type II, the article notes that jaundice can be set off by infection, anaesthesia or the use of certain drugs, so it is sensible for anyone with the condition to make sure clinicians know about it before procedures or new prescriptions.

The main sign is jaundice. The NHS says that for newborns, yellow skin and eyes usually show first on the face and head and can be harder to see on black or brown skin, and that parents should seek urgent advice if jaundice is not getting better or is getting worse, if urine is dark yellow or brown or if stools are pale.

In type I the jaundice is persistent and marked. The danger is kernicterus, damage to the brain from very high bilirubin. The professional article lists low muscle tone (hypotonia), deafness and problems with eye movements among its manifestations. For babies the NHS lists signs that need an emergency response, including being sleepier than normal or difficult to wake, not feeding, being floppy or stiff, or having jerking movements, and advises calling 999 or going to A&E.

Diagnosis begins with blood tests. Total bilirubin is raised, with unconjugated bilirubin predominating, while other liver function tests are usually normal. Doctors also need to rule out more common causes of newborn jaundice such as haemolysis, Gilbert's syndrome, breast-milk jaundice and hepatitis.

Genetic testing can detect the mutations in the UGT1A1 gene that cause the condition, although the article notes this is done only at specialised laboratories. A response, or lack of response, to phenobarbital also helps separate type I from type II. In the UK, a baby with persistent or severe jaundice would normally be assessed by a paediatric team and then by a specialist liver or metabolic centre.

Treatment depends on the type. In type I, early control of bilirubin is needed to avoid kernicterus. The professional article describes aggressive phototherapy and exchange transfusions in the newborn period. The NHS describes phototherapy as shining a special light on the skin, usually done in a cot in hospital, and says most babies with ordinary newborn jaundice need around 48 hours of it; the reference article describes it as a mainstay of management in type I.

During a crisis with toxic bilirubin levels, treatment can include intravenous fluids, albumin and plasma exchange, and plasmapheresis is described as the most effective way to remove excess bilirubin. Medicines such as calcium phosphate and ursodeoxycholic acid are used in some cases. Some experimental treatments and gene therapy are described as possible future options.

Liver transplantation is currently the only specific treatment. NHS Blood and Transplant describes a liver transplant as a major operation in which a diseased liver is replaced by a donor liver, with assessment, a waiting list and surgery as the main stages. The article says that results are better when transplantation is done before neurological damage develops.

In type II usually no treatment is needed. Phenobarbital can be used if bilirubin is persistently high, and during crises phototherapy or exchange transfusion may be used to prevent encephalopathy. Certain drugs that displace bilirubin from protein binding, such as sulfonamides, salicylates and penicillin, should be avoided.

The professional article says type I once had an appalling prognosis, with death by the age of two. With phototherapy, plasma exchange and the possibility of liver transplantation, survival into the teens or early adulthood is now more usual. It also notes that the effectiveness of phototherapy tends to fall in the teenage years, which can make management hard if transplantation is not possible. People with type II should have a normal or near-normal life expectancy.

Because the condition is so rare, care is usually led by specialist paediatric liver or metabolic teams, and NHS Blood and Transplant lists seven liver transplant centres in the UK. Families are typically referred there by their local paediatric team.

Because of the genetic basis, families can ask their specialist team about genetic counselling and the chances for future pregnancies.