Crigler Najjar Syndrome: Symptoms, Causes & Treatment

Crigler-Najjar syndrome is a rare genetic disorder that affects the liver’s ability to process bilirubin. Bilirubin is a yellow pigment which is produced when red blood cells break down.
The liver converts bilirubin from a toxic substance (unconjugated bilirubin) to a nontoxic substance (conjugated bilirubin). People get rid of the nontoxic bilirubin in their stool. 

The liver cannot break down toxic bilirubin in people with Crigler-Najjar syndrome. As a result, they have a buildup of toxic bilirubin in their blood. 

Crigler-Najjar syndrome is typically categorised into two main types. The classification is based on the severity of the syndrome. These two types include:

1. Type 1 (CN1): Crigler-Najjar syndrome type 1 is a very severe form of the disease. The condition is life-threatening.
   Most children die in childhood due to disease complications, such as kernicterus (brain damage caused by jaundice). 

2. Type 2 (CN2): Crigler-Najjar syndrome type 2 is less severe than CN1. Children diagnosed with type 2 are less likely to develop kernicterus.
   Most children with this type have a normal life expectancy and survive into adulthood. 

Crigler-Najjar syndrome symptoms differ in severity based on the type. The symptoms of CN1 become apparent shortly after the birth of the child.
Newborns with Crigler-Najjar syndrome develop severe jaundice (yellowing of the skin and eyes). 

It is common for infants to have jaundice, which generally resolves during the first week. However, children with this syndrome experience jaundice that persists beyond the first three weeks of life.
Infants risk developing kernicterus, called bilirubin encephalopathy, within the first month or early childhood. Kernicterus is a type of brain damage that results from high bilirubin levels in the baby’s blood. 

Mild symptoms of kernicterus may include the following neurological or movement problems:

1. Clumsiness (poor coordination, movement, or action)

2. Muscle spasms (painful contractions and tightening of the muscles)

3. Difficulty with fine motor skills (playing with fingers, grasping objects, etc.)

4. The trouble with sensory perception (the brain has trouble processing information from the senses)

5. Choreoathetosis (involuntary twisting movements of the body)

Severe symptoms of kernicterus include:

1. Hearing loss

2. Extreme fatigue or lack of energy (lethargy)

3. Severe muscle spasms, causing arching of the back

4. Nausea or vomiting

5. Fever

6. Difficulty with feeding

7. Problems with cognitive development

8. Hypertonia (episodes of increased muscle tone) or hypotonia (weak muscle tone)

Crigler-Najjar syndrome causes include mutations in the UGT1A1 gene. This genetic mutation affects the production or function of the bilirubin uridine diphosphate glucuronosyltransferase (bilirubin-UGT) enzyme.
Crigler-Najjar syndrome pathophysiology is as follows:

1. The bilirubin-UGT enzyme, primarily found in the liver cells, transfers glucuronic acid to unconjugated (toxic) bilirubin, converting it to conjugated (nontoxic) bilirubin. 

2. This process makes bilirubin soluble and easier to excrete from the body.  

3. The specific genetic mutations associated with Crigler-Najjar Syndrome disrupt the normal activity of the bilirubin-UGT enzyme, leading to impaired bilirubin processing.

4. Individuals with type 1 of the syndrome have no enzyme function, whereas individuals with type 2 have less than 20% of normal enzyme function. 

5. The loss of enzyme function prevents the body from converting bilirubin into its nontoxic form, causing a toxic substance buildup in the blood. 

Crigler-Najjar Syndrome Risk Factors

The primary risk factor for Crigler-Najjar syndrome is having a family history of the condition. It is an inherited genetic disorder passed down from parents to their children.
Crigler-Najjar syndrome inheritance follows an autosomal recessive pattern, i.e., both parents must carry a copy of the UGT1A1 mutated gene for their child to be affected.

If only one parent passes the mutated gene to the child, the mutation may cause a less severe condition called Gilbert syndrome.
The number of inherited UGT1A1 mutated genes is the primary difference between Gilbert syndrome vs Crigler-Najjar syndrome. 

Currently, there is no known way to prevent the development of Crigler-Najjar syndrome, as it is a genetic disorder caused by specific gene mutations.
However, some steps can help reduce the risk of passing these gene mutations to future generations. These measures include:

1. Regular Monitoring: Individuals with Crigler-Najjar syndrome require ongoing monitoring of their bilirubin levels.
   Blood tests can help assess the concentration of toxic bilirubin in the bloodstream.

2. Genetic Counselling: People who have a family history of Crigler-Najjar syndrome should consider genetic counselling before planning to become pregnant.
   Genetic counsellors can help couples understand the risk of passing the condition to their children. They may also provide information about family planning options.

Severe jaundice within the first few days to weeks of birth may result in suspicion of the syndrome. The healthcare provider will conduct a physical exam and evaluate the individual’s medical history.
The healthcare provider may recommend some tests to confirm the Crigler-Najjar syndrome diagnosis. These diagnostic tests include:

1. Bilirubin Blood Tests: The doctor may perform blood tests to detect the total bilirubin level in the patient’s blood.

2. Blood and Stool Tests: Tests like liver function tests or a complete blood count help determine the level of unconjugated bilirubin in the patient’s blood and stool.
   In type 1 of the syndrome, the unconjugated bilirubin level is between 20 and 25 mg/dL and 50 mg/dL for severe cases. In type 2, the level is generally less than 20 mg/dL. 

3. Genetic Testing: It can confirm the diagnosis of Crigler-Najjar syndrome and identify specific mutations in the UGT1A1 gene.
   Genetic testing involves analysing a sample of the individual’s DNA, usually obtained through a blood sample or cheek swab.

4. Liver Biopsy: Sometimes, doctors may perform a liver biopsy to evaluate or rule out other liver diseases like liver cirrhosis. 

How to Prepare for Doctor’s Consultation?

Preparing for a doctor’s consultation for Crigler-Najjar syndrome can help individuals make the most of their appointment and address their concerns effectively. Here are some tips to help them prepare:

1. Note Down Symptoms: Patients must note down the symptoms they experience and their duration. 

2. Make a List of Medications: Enlisting the medication, supplements, and herbs the patient takes is recommended.
   This helps the doctor understand if there are any drug interactions. 

3. Know the Family History: Crigler-Najjar syndrome is a genetic condition.
   So patients must be prepared to provide detailed information about the family history of the disorder.

4. Write Questions for the Doctor: Noting questions beforehand will ensure that the patient covers all the important topics during the appointment.
   This helps them receive the necessary information.

5. Bring a Friend or Family Member: Patients should consider taking a friend or family member to the appointment.
   They can offer support and help remember important information. 

What to Expect from the Doctor?

During a Crigler-Najjar syndrome appointment, the doctor may ask several questions to gather relevant information about the patient’s health and medical history.
Here are some questions that the doctor may ask:

1. When did you or your child first notice the onset of jaundice?

2. Do you experience any other symptoms of jaundice, such as fatigue, weakness, or neurological symptoms?

3. Does anything seem to improve or worsen jaundice or affect overall health?

4. Do you have a family history of Crigler-Najjar syndrome?

5. How frequently are your bilirubin levels monitored, and what are the typical levels?

6. Have you considered or undergone genetic testing or counselling?

Questions to Ask the Doctor

Asking questions during a Crigler-Najjar syndrome appointment can help better understand the condition, treatment options, and management strategies.
Here are some questions individuals may consider asking the doctor:

1. What type of Crigler-Najjar syndrome does my child have?

2. How often should bilirubin levels be monitored, and what level is considered safe?

3. What are the available treatment options, and which one do you recommend?

4. What is the goal of treatment for Crigler-Najjar syndrome?

5. Are there any side effects of these treatments?

6. How long will my child need phototherapy?

7. Does my child need a liver transplant?

8. Are there any potential complications associated with the disease that I should be aware of?

9. Are there any lifestyle modifications or dietary recommendations to help manage the condition?

10. Should I consider genetic counselling for myself or my family members?

The main goal of treatment for Crigler-Najjar syndrome is the reduction of bilirubin levels in the body. The treatment options for type 1 and type 2 of the syndrome may differ.
Treatment could include:

1. Phototherapy: The primary Crigler-Najjar syndrome type 1 treatment is phototherapy.
   In this procedure, the skin is exposed to bright lights to remove bilirubin from the body.
   
   The light moves bilirubin through the body into the bile and intestines for elimination without converting it into its conjugated form.
   The treatment is less effective in older children and adults due to increased skin pigmentation and thicker skin.

2. Plasmapheresis: It is the most effective treatment for removing excess unconjugated bilirubin from the blood.
   In this procedure, the patient’s blood is removed, and blood cells are separated from plasma.
   
   The plasma is replaced with healthy plasma, usually from a donor, and the blood is transferred to the patient. 

3. Medicines: The doctor may prescribe medications to treat infections or illnesses resulting in fever. 

4. Liver transplantation: This is the only definitive treatment for type 1 of the syndrome.
   It is a surgical procedure in which the patient’s liver is removed and replaced with a healthy donor liver. 

   The transplanted liver has a healthy UGT1A1 enzyme, which reduces serum bilirubin levels. A liver transplant is usually done before adolescence to prevent kernicterus.  

5. Phenobarbital: Therapy with phenobarbital prevents bilirubin buildup in the blood. It effectively treats Crigler-Najjar syndrome type 2, reducing the serum bilirubin level by 25%. 

Please Note: The selection of the treatment approach is based on the patient’s disease type and condition and the treating doctor’s opinion. 

Cost of Crigler-Najjar Syndrome Treatment

The cost of the Crigler-Najjar syndrome treatment in India varies on several factors, including the patient’s age, other comorbidities, type of the condition, doctor’s expertise, type and location of the hospital and much more.

To know the exact cost of the Crigler-Najjar syndrome treatment in India, one must consult their doctor.
However, the below table also provides the approximate cost of the treatment modalities for the Crigler-Najjar syndrome.

Prognosis of Crigler-Najjar Syndrome

Crigler-Najjar syndrome prognosis can vary depending on several factors. These factors include the type, the severity of the condition, and the individual’s response to treatment.
The prognosis for the types of syndrome is as follows:

1. Infants with a mild form of the disease (type 2) experience fewer symptoms and less organ damage.
   Individuals with type 2 syndrome will have a good prognosis with early treatment. 

2. Infants with a severe form of the disease (type 1) will have a poor diagnosis if the condition is not diagnosed and treated within the first few months of birth.
   Children have a risk of developing life-threatening symptoms, preventing them from living more than two years. 

Most individuals with this syndrome require lifetime treatment. With effective treatment and management, people can have a normal life expectancy.

The Crigler-Najjar syndrome can lead to various complications. It is especially true if the condition is not properly managed or if bilirubin levels remain elevated over an extended period.
Here are some potential complications associated with Crigler-Najjar syndrome:

1. Kernicterus: It refers to the deposition of unconjugated bilirubin in the brain, leading to neurological damage. Severe and prolonged elevation of bilirubin levels, probably above 25 mg/dL, increases the risk of kernicterus. 

   It is more commonly seen in type 1 of Crigler-Najjar syndrome, but patients with type 2 can also develop this complication. 

2. Chronic Jaundice: Individuals can develop chronic jaundice when the syndrome is persistent, and the diagnosis is delayed. The limited bilirubin excretion causes the serum level to increase progressively. 

3. Cholelithiasis: Increased levels of unconjugated bilirubin can cause gallstone formation later in life. 

4. Liver Cirrhosis: This is not a direct complication of Crigler-Najjar syndrome. A baby born with this syndrome has a healthy liver in most cases.

The exact mechanisms by which liver cirrhosis occurs are not fully understood. However, it may develop due to:

1. Chronic biliary obstruction after cholelithiasis

2. Toxicity from drugs metabolised in the liver

3. Toxicity from phototherapy

When to See a Doctor?

It is important to consult a healthcare professional if an individual or their child exhibits symptoms or signs of Crigler-Najjar syndrome, such as persistent jaundice.
Some additional symptoms that may require seeking medical attention include:

1. High fever

2. Persistent jaundice after phototherapy

3. Developmental delays

4. Difficulty eating

While no specific diet can cure Crigler-Najjar syndrome, certain considerations may be helpful.
Patients must consult with a healthcare provider or registered dietitian to receive personalised advice based on their needs.
Here are some general dietary recommendations:

Foods to Eat

1. High-Carbohydrate Foods: People with Crigler-Najjar syndrome cannot process fats and proteins.
   Therefore, they should eat more carbs to compensate for fats and proteins.
   Sources of carbohydrates include vegetables, fruits, legumes, and whole grains. 

2. Nutrient-Rich Foods: Foods high in nutrients can help improve general health and prevent deficits.
   Examples include fruits, vegetables, nuts, seeds, whole grains, and lean protein sources. 

3. Fluids: Drinking lots of fluids, especially water, can help avoid dehydration and promote good liver function. 

Foods to Avoid

1. High-Fat Foods: Individuals with Crigler-Najjar syndrome may have trouble digesting high-fat foods.
   Processed meats or fried foods can affect liver function and worsen the symptoms. 

2. Sugar: Consuming excessive sugar (in the form of sugary drinks or refined sugar) can cause individuals to experience liver issues. Therefore, high intake of sugar must be avoided. 

3. Alcohol: Regular and high consumption of alcohol can cause liver damage and worsening symptoms.

Crigler-Najjar syndrome is a rare genetic disorder characterised by impaired bilirubin metabolism, resulting in elevated bilirubin levels. It can lead to jaundice and requires lifelong management.
Differentiating Gilbert syndrome vs Crigler-Najjar syndrome is important for accurate diagnosis and appropriate treatment.

If you or a loved one is affected by Crigler-Najjar syndrome, the HexaHealth team can provide valuable support. Our expert healthcare professionals can offer comprehensive guidance, personalised treatment plans, and ongoing monitoring.
Furthermore, we can connect you with relevant resources to enhance your quality of life. Contact us TODAY!

Suggested Reads