Crigler-Najjar Syndrome - Causes, Symptoms, and Treatment

Introduction

Crigler-Najjar syndrome was first reported in the medical literature in 1952 by Dr. Crigler and Najjar. Crigler-Najjar syndrome is a genetic disorder that occurs due to the inability of the liver to convert and excrete bilirubin from the body. The most important finding of this disease is the yellowish discoloration of the skin, eyes, and mucous membranes. This disease equally affects males and females. The incidence of this disease is fewer than one in one million newborns.

What Is Bilirubin?

Bilirubin is a yellowish-orange substance produced when the old and mature red blood cells are broken down during hemolysis. The liver converts the bilirubin produced during hemolysis from a toxic unconjugated form to an easily dissolvable conjugated form.

What Is Crigler-Najjar Syndrome?

Crigler-Najjar syndrome is a severe hereditary disease that causes congenital non-hemolytic jaundice. In this condition, the liver can not break the bilirubin leading to increased levels of toxic bilirubin in the blood (unconjugated hyperbilirubinemia). The unconjugated bilirubin gets collected in the liver and spleen, causing nerve and brain damage if left untreated.

What Are the Other Names for Crigler-Najjar Syndrome?

Crigler-Najjar syndrome is also known as follows:

• Familial non-hemolytic unconjugated hyperbilirubinemia.

• Hereditary unconjugated hyperbilirubinemia.

How Is Crigler-Najjar Syndrome Classified?

There are two types of Crigler-Najjar syndrome. They are:

1. Crigler-Najjar Syndrome Type 1 - It is very severe and has serious complications. Most children with this condition will not survive childhood.

2. Crigler-Najjar Syndrome Type 2 - It is less severe than type 1, and patients show mild symptoms, also called Arias syndrome.

What Causes Crigler-Najjar Syndrome?

The syndrome occurs due to genetic defects in the bilirubin-uridine diphosphate glucuronosyltransferase (UGT1A1) gene. This results in the absence or decreased levels of the UDP-glucuronosyltransferase enzyme, which is responsible for the breakdown and elimination of bilirubin from the body.

The common mutations in type-1 Crigler-Najjar Syndrome are deletions, exon skipping, alterations in the intron splice donor and receptor sites, missense mutations, insertion, or formation of a stop codon within the UGT1A1 gene. Type 2 Crigler-Najjar syndrome occurs due to a point mutation in the UGT1A1 gene.

Crigler-Najjar syndrome is an autosomal recessive disorder. It occurs when an individual inherits two copies of the abnormal gene, one from each parent (closely related parents have a higher risk of passing a recessive genetic disorder to the children).

What Are the Symptoms of Crigler-Najjar Syndrome?

The symptoms of Crigler-Najjar syndrome appear shortly after birth or develop three weeks after birth. The symptoms include the following:

1. Severe yellowish skin discoloration, mucous membrane, and eyes (jaundice).

2. Infants with type 1 disease develop kernicterus, also called bilirubin encephalopathy. Kernicterus is a life-threatening condition in which elevated levels of toxic bilirubin accumulate in the brain causing brain damage in newborns. The symptoms of kernicterus are:

• Lethargy or extreme fatigue.

• Vomiting.

• Fever.

• Mild or severe muscle spasms in which the body is bent forward and the head and heels are bent backward (opisthotonus).

• Spasticity (uncontrolled muscle movements).

• Hypotonia (decreased muscle tone) causing floppiness.

• Feeding difficulties in infants.

• Clumsiness.

• Underdeveloped enamel of the teeth.

• Hearing loss.

• Sensory perception problems.

• Convulsions.

• Athetosis (involuntary movement of the arms, legs, or entire body).

• Brain damage.

3. Type 2 Crigler-Najjar syndrome shows milder symptoms than type 1. Kernicterus is rare in type 2. Infants suffer from this syndrome when they are sick, under general anesthesia, or in prolonged starvation.

How Is Crigler-Najjar Syndrome Diagnosed?

Crigler-Najjar syndrome diagnoses include clinical examination, patient history, and diagnostic test procedures. The diagnostic tests are as follows:

1. Serum unconjugated bilirubin level testing helps to measure the level of unconjugated bilirubin. In type 1, the level of serum unconjugated bilirubin is between 20 and 25 milligrams per 100 milliliters of blood, whereas, in type 2, it is less than 20 milligrams per 100 milliliters of blood.

2. Bile analysis shows no detectable bilirubin glucuronides.

3. Urine analysis helps to detect a lack of bilirubin in urine.

4. Molecular genetic testing is a confirmation diagnostic test for Crigler-Najjar syndrome. It detects mutations in the UGT1A1 gene.

5. Tissue enzyme assay of a liver biopsy can measure the level of UGT enzyme.

6. Phenobarbital administration helps to distinguish between type 1 and type 2 Crigler-Najjar syndrome. Phenobarbital is a barbiturate that reduces blood bilirubin levels in Crigler-Najjar syndrome type 2 and Gilbert syndrome. It is ineffective in cases of type 1 Crigler-Najjar syndrome, thus helping in distinguishing type 1 and type 2.

What Is the Differential Diagnosis for Crigler-Najjar Syndrome?

The other conditions causing unconjugated hyperbilirubinemia include:

• Hemolysis - This occurs in sickle cell disease causing increased production of bilirubin.

• Ineffective Erythropoiesis - Increased bilirubin production occurs in thalassemia, pernicious anemia, and iron deficiency anemia.

• Gastrointestinal Bleeding and Hematoma - Blood resorption from gastrointestinal bleeding and hematoma cause unconjugated hyperbilirubinemia.

• Gilbert Syndrome - The most common form of inherited hyperbilirubinemia occurs due to a defect in the promoter region.

• Lucey-Driscoll Syndrome - It occurs due to some compounds in the blood that block the bilirubin breakdown.

• Rotor Syndrome - A rare inherited disorder with high levels of conjugated bilirubin.

• Dubin-Johnson Syndrome - Inherited disorder occurs due to a mutated ABCC2 gene showing elevated levels of conjugated bilirubin.

How Is Crigler-Najjar Syndrome Treated?

The treatment for Crigler-Najjar syndrome mainly focuses on lowering the serum bilirubin level. The treatment options include:

1. Phototherapy - Intensive phototherapy is an effective treatment for Crigler-Najjar syndrome. Bright lights remove bilirubin from the body without changing it into its non-toxic form.

2. Plasmapheresis - It is a process of removing excess unconjugated bilirubin from the blood by blood transfusion.

3. Orlistat - It is a lipase inhibitor used to capture unconjugated intestinal bilirubin and excretes them.

4. Calcium Phosphate Supplementation - Oral calcium phosphate supplementation helps to decrease the serum bilirubin level.

5. Liver Transplant - It is the only definitive treatment option for Crigler-Najjar syndrome type 1. This surgical procedure replaces the defective liver with a healthy one with a normal UGT1A1 gene, reducing serum bilirubin levels.

6. Gene Therapy - Normal UGT1A1 genes are transduced into the cultured hepatocytes.

7. Phenobarbital - It prevents bilirubin from building up in the blood. It is effective for the treatment of Crigler-Najjar syndrome type 2.

Conclusion

Crigler-Najjar syndrome cannot be prevented as it is a genetic condition. However, this disease shows a good prognosis if it is diagnosed and treated earlier. People diagnosed with Crigler-Najjar syndrome will need lifelong treatment and management to have a normal lifespan. Studies show that liver transplantation is an effective cure for Crigler-Najjar syndrome.