Crigler-Najjar Syndrome: Causes, Symptoms & Treatment

Crigler-Najjar syndrome is an extremely rare inherited disorder. Patients with this disorder have impaired blood metabolism because of decreased activity of the enzyme UDP-glucuronyl transferase. Therapeutic options range from phototherapy to liver transplantation.

What is Crigler-Najjar syndrome?

Crigler-Najjar syndrome is the medical term for a congenital and extremely rare disease of hemoglobin metabolism. Bilirubin is a waste product of hemoglobin and is 90 percent albumin-bound and primary in serum in healthy individuals. In patients with Crigler-Najjar syndrome, the concentration of unconjugated bilburin increases. The activity of the bilirubin-processing UDP-glucuronyl transferase enzyme is severely impaired due to a mutation. This mainly shows pathological effects on the liver. The prevalence of this disease is reported to be one in a million. The disease was named after the physicians John Fielding Crigler and Victor Assad Najjar. They first described the syndrome in the 20th century. According to modern medical knowledge, two forms of Crigler-Najjar syndrome can be distinguished, referred to as CN type I and CN type II.

Causes

The cause of Crigler-Najjar syndrome is a genetic defect. According to current research, both the first and second types of the disorder are caused by a defect in the UGT1 gene, which is located on chromosome two. Specifically, the first type is a mutation of exons two through five of the corresponding gene. This type of the disease is inherited autosomal recessively. This means that two carriers of the unaffected gene defect have the same chance of having a healthy child as they do of having a sick child. To pass on the mutation, both parents must be carriers of at least the defective allele. Type two of Crigler-Najjar syndrome, on the other hand, is passed on in the autosomal dominant mode of inheritance. In this mode of inheritance, one defective gene is sufficient for inheritance.

Symptoms, complaints, and signs

Both forms of Crigler-Najjar syndrome are characterized by a condition called jaundice. The patient’s skin, mucous membranes, and internal organs turn yellowish because of undegraded bilirubin. In addition to the processing of bilirubin, that of drugs and steroid hormones is also disturbed. All other liver values of the patients are in the normal range. In the first type of the syndrome, enzyme activity is zero or severely reduced. Icterus in this form occurs immediately after birth. Bilirubin is hardly metabolized and is excreted in the stool only in small amounts. Even administration of UDP-glucuronyl transferase enzyme fails to lower plasma bilirubin elevation. Type II of the syndrome is somewhat milder. The residual activity of the enzyme is about ten percent and induction of the UDP-glucuronyl transferase enzyme can reduce the elevation of bilirubin in plasma.

Diagnosis and course

Physicians usually diagnose Crigler-Najjar syndrome during the collection of liver tests and blood work. The course of the disease differs with the type. In type I, medicine basically assumes an unfavorable course. In this form of the disease, the storage of the excess bilirubin affects the central nervous system. This leads to bilirubin encephalopathy. In medical terms, this is the penetration of bilirubin into nerve fibers and the brain. Severe neurological deficits develop as part of this phenomenon. Most type one patients therefore die during childhood. In type II patients, the prognosis is more favorable. In most cases, icterus attacks only the skin in their case. This can reduce the quality of life due to persistent itching. However, premature death is not expected.

Complications

Neurologic complications are not uncommon in an inherited disease affecting the liver such as Crigler-Najjar syndrome type 1. In this severe form of liver disease, postnatal jaundice secondary to hyperbilirubinemia is the most serious complication. In the milder type of the disease, known as Arias syndrome, serious complications are not as common. Icterus may manifest itself in this case as well. However, it is milder due to the enzyme residues that are still active. As a result, it can be better treated. Nevertheless, the quality of life is always limited by Crigler-Najjar syndrome.In the most severe case of Crigler-Najjar syndrome type 1, the newborn patient must be treated immediately. Treatment of postnatal complications may require early liver transplantation in those affected with Crigler-Najjar syndrome of this type. Before that becomes necessary, however, treating physicians try to prevent further sequelae of Crigler-Najjar syndrome with conservative treatment approaches. Possible neurological sequelae should be suppressed or at least delayed. If this is not successful, liver transplantation is unavoidable. This operation carries high risks in newborns. The extent to which allogeneic transplantation of liver cells proves helpful and life-saving in Crigler-Najjar syndrome type 1 has not yet been adequately studied. Provided that daily phenobarbital is administered in Crigler-Najjar type 2 syndrome, disease-related complications can be avoided.

When should you see a doctor?

A physician should be consulted if symptoms of jaundice or noticeably severe itching occur. The conspicuous discoloration of the skin indicates a disease that must be clarified in any case and treated if necessary. The physician can determine whether this is Crigler-Najjar syndrome on the basis of a medical history and liver and blood values. At the latest, if complications become apparent, an immediate visit to the doctor is indicated. With children who show neurological abnormalities, it is best to go directly to the pediatrician. In case of cardiovascular complaints and signs of failure such as circulatory collapse or coma, the emergency physician must be alerted immediately. Crigler-Najjar syndrome usually becomes apparent in early childhood. Parents who themselves suffer from a hereditary disease or have cases of the syndrome in their immediate family or relatives should consult a doctor immediately if they experience the symptoms mentioned. In addition to the general practitioner, specialists for hereditary diseases, neurologists or internists are further contacts. If the child is affected, psychological support should be sought at an early stage.

Treatment and therapy

Measures for therapy of Crigler-Najjar syndrome differ by type. In type II patients, the physician usually advises administration of the epilepsy drug phenobarbital. This administration takes place once a day for life. The drug is supposed to stimulate the enzyme activity and thus lower the bilirubin concentration in the plasma in a harmless way. For type one patients, the therapy usually consists of three different pillars. Typically, they participate in what is called blue light therapy once a day. This treatment measure makes the bilirubin water-soluble. The drug Tinprotoporphyrin is administered to attenuate the increase in the now water-soluble bilirubin. The drug is an inhibitor of heme oxygenase. This heme oxygenase is an enzyme for breaking down heme to iron. These two therapeutic measures are usually rounded off by the administration of calcium carbonate and calcium phosphate. This is to release the bilirubin from the organism to the intestine. The excretion of the excess substance is thus stimulated. This three-part therapy prolongs the life expectancy of patients. The expected complications in the neurological field can at least be delayed with these therapeutic measures. Under certain circumstances, liver transplantation may also be useful for patients of the first type. This transplantation should ideally be performed relatively early. Stem cell therapeutic approaches are still being tested in this context. There is as yet no causative treatment and thus no prospect of a cure for Crigler-Najjar syndrome. However, advances in gene therapy may change that in the near future.

Prospect and prognosis

The further course of Crigler-Najjar syndrome depends very much on its exact expression, so a general prediction is not possible in this regard. In many cases, the epileptic seizures are limited with the help of medication. Furthermore, many affected persons depend on phototherapy to limit the symptoms. Treatment of the syndrome significantly increases the life expectancy of the patient, although a complete cure cannot be achieved. In severe cases, sufferers rely on a liver transplant to continue to survive. In many cases, this must be performed at a young age.If Crigler-Najjar syndrome is not treated, it usually leads to the death of the affected person or to a significantly reduced life expectancy. A causal treatment of the syndrome is not possible, so that only the symptoms can be limited. Parents should undergo genetic counseling if they wish to have another child, in order to prevent the syndrome from recurring in a child. Since many of the surgical procedures must take place immediately after birth, they are associated with high risks.

Prevention

Crigler-Najjar syndrome is a gene mutation. Therefore, the condition cannot be prevented. However, as part of a DNA sequence analysis, couples in family planning can have the likelihood of having a child with the disease estimated.

Follow-up

In Crigler-Najjar syndrome, there are usually few measures of aftercare available to the affected person. In this disease, the affected person is primarily dependent on a rapid and, above all, early diagnosis so that no further complications occur and the symptoms of the disease do not continue to worsen. Since Crigler-Najjar syndrome is a hereditary disease, it cannot be completely cured, so that the patient is dependent on lifelong therapy. If the patient wishes to have children, genetic counseling is highly recommended to prevent the recurrence of this disease in the descendants. Self-cure cannot occur in this syndrome. Since the treatment is often carried out with the help of medications, the patient should always pay attention to a regular intake with a correct dosage. Regular examinations by a doctor are also very important in order to monitor the symptoms permanently. In severe cases of the disease, however, the transplantation of a liver may also be necessary, so that the life expectancy is also not infrequently reduced by Crigler-Najjar syndrome. Loving care and support from one’s family is very important to prevent depression or other psychological upsets.

Here’s what you can do yourself

Patients with Crigler-Najjar syndrome are severely impaired in their daily lives. While type CN II sufferers usually only need to pay attention to medication adherence, phototherapy is the main factor that determines daily life for CN I patients. Sleeping unclothed for maximum exposure to light during the cold season means that sufferers often freeze at night. In summer, the heat radiation of the blue light device can disturb sleep. Modern devices with LED lighting and significantly reduced heat generation provide a remedy. In general, care must be taken to ensure flexible air conditioning in the sleeping area and the fit of the goggles must be checked. Water and salt losses due to increased evaporation as a result of the light energy must be compensated. Due to several hours of phototherapy, other activities are severely limited. Due to the size and lack of transportability of the therapy units, vacation trips are also difficult to realize. However, portable units are now available. In individual cases, affected patients can also be treated using fiber-optic light mats. For affected children and adolescents, the external appearance of Crigler-Najjar syndrome often leads to problems in contact with other children. Parents and relatives suffer along not only with teasing, etc. They are also further burdened by the need for regular monitoring during nighttime phototherapy.