What is Crigler-Najjar Syndrome?
Crigler-Najjar syndrome is a rare genetic disorder that causes high levels of bilirubin in newborn babies. Bilirubin is a compound that our bodies make when we break down red blood cells, and it is usually removed by the liver. However, due to this disorder, the liver cannot effectively remove bilirubin, leading to its build-up in the baby’s system.
This syndrome is associated with a deficiency or absence of a specific enzyme in the liver necessary for processing bilirubin. The decrease in this enzyme results in a type of yellowing of the skin, termed congenital nonhemolytic jaundice.
Crigler-Najjar syndrome is of two types, mainly based on enzyme activity. Type 1 is severe wherein the enzyme activity is minimal or absent. As a result, babies with type 1 syndrome face severe or extremely serious symptoms of jaundice. Babies with this type of syndrome have to regularly undergo phototherapy, a type of treatment that uses light to break down bilirubin in the body. They also have a very high chance of developing damage to the nervous system, including permanent damage called kernicterus. A liver transplant is the only complete cure for this type of syndrome.
Type 2 of the syndrome is less severe, characterized by reduced enzyme activity leading to milder symptoms. Affected individuals experience occasional jaundice triggered by stress and typically control the condition with careful monitoring and management. The potential for permanent nervous system damage in this type is rare, and a liver transplant is not usually needed.
What Causes Crigler-Najjar Syndrome?
Crigler-Najjar syndrome occurs when there is a lack or even an absence of a particular enzyme called UGT due to a fault in a specific gene. This gene is called bilirubin UDP-glucuronosyltransferase family 1, polypeptide A1 – or UGT1A1 for short.
Two types of this syndrome exist, CN1 and CN2. In CN1, the fault in the UGT1A1 gene can take many forms. It might involve partial or complete removal of parts of the gene, changes in the spots where different gene segments connect, accidentally skipping parts of the gene, or adding in something extra. Any of these can cause a total lack of the UGT enzyme.
On the other hand, CN2 is caused by a slight change in the UGT1A1 gene, resulting in a decreased production of the UGT enzyme rather than a complete absence.
Risk Factors and Frequency for Crigler-Najjar Syndrome
Crigler-Najjar syndrome is a very rare disease that affects newborn babies, with only 0.6 to 1 cases in every 1 million babies born worldwide. Although it’s rare, it needs careful medical attention due to the severe effects related to high bilirubin levels in those with the condition.
Signs and Symptoms of Crigler-Najjar Syndrome
Crigler-Najjar syndrome or CN1 is a condition that can cause significant yellowing of the skin or eyes in newborns, a condition known as jaundice. The jaundice usually appears and worsens within the first few days to the second week after birth. It might be more likely if there’s a family history of severe jaundice, liver diseases, or relatives who’ve had to have treatment to remove bilirubin from their body. Jaundice is primarily caused by a compound called unconjugated bilirubin, usually present in levels between 20 to 25 mg/dL, though some cases can reach up to 50 mg/dL. One sign of this condition is yellowish skin and eyes, but the stool color remains normal. However, the body might excrete less urobilinogen, a byproduct of bilirubin breakdown. Outside of jaundice, patients show no signs of liver diseases but older children might have scratch marks due to severe itching. Some people might have enlarged liver and spleen due to progressive liver dysfunction and toxic effects.
The abnormally high levels of bilirubin can also lead to neurological symptoms due to its toxic effects on specific regions of the brain controlling eye and auditory functions. The acute effects, known as Acute Bilirubin Encephalopathy (ABE) include sleepiness, decreased muscle tone, and a high-pitched cry. If bilirubin remains high, symptoms may progress to fever, lethargy, poor feeding, irritability, and increased muscle tone leading to unusual body postures. It can lead to seizures, difficulty breathing or even a comatose state in severe cases. Brainstem auditory-evoked responses (BAER) is a test that can detect these acute neurological dysfunctions.
Over time, Chronic Bilirubin Encephalopathy (CBE), also known as kernicterus, can become apparent. This condition may lead to uncontrolled and purposeless movements, hearing loss, gaze abnormalities, and underdevelopment of tooth enamel, although cognitive function usually remains unaffected. If suspected, magnetic resonance imaging (MRI) of the brain can show alterations in some parts of the brain.
CN2 is a similar, but milder condition with fewer and less severe symptoms. Patients with CN2 need to have regular assessments to monitor levels of bilirubin in their body and their liver function to manage the condition effectively and to detect potential complications as early as possible.
Testing for Crigler-Najjar Syndrome
If doctors suspect someone has Crigler-Najjar syndrome, they will usually measure the amount of a substance called unconjugated bilirubin in the person’s blood. Patients with type 1 Crigler-Najjar usually have levels of unreleased bilirubin between 2 and 25 milligrams per deciliter (mg/dL). In severe cases, this can elevate to 50mg/dL. In comparison, people with type 2 of the syndrome usually showcase bilirubin levels below 20 mg/dL.
Doctors used to collect samples for bile examination using procedures like a top-down inspection and test of the digestive tract or a tube inserted into the small intestine, alongside a sophisticated type of testing known as high-performance liquid chromatography (HPLC). In contrast, diagnosis today is more likely to involve genetic testing methodologies.
The administration of a medicine called phenobarbital for two weeks has been found to reduce bilirubin concentration in most patients with Crigler-Najjar type 2. This treatment, however, doesn’t help those with type 1 of the syndrome.
Genetic analysis is a critical diagnostic tool for identifying the presence of abnormal genes in different samples, including blood cells, cells scraped from the inside of the mouth, and tissues from different body areas. This kind of analysis can be used to detect mutations in the gene that makes the UGT enzyme. This enzyme is not functional in people with Crigler-Najjar syndrome. Moreover, using genetic evaluation, the disease can also be identified before a baby is born with the help of samples from the placenta or the fluid surrounding the baby in the womb.
In addition, advanced brain imaging techniques, such as diffusion tensor imaging, may help identify subtle changes in the structure of the brain in Crigler-Najjar type 1 patients. Similarly, a liver biopsy, which involves taking a small piece of liver tissue for examination, can be helpful to assess the presence of liver scarring, or cirrhosis, in cases where patients may have unusually large liver and spleen sizes.
Treatment Options for Crigler-Najjar Syndrome
The main goal of treating people with Crigler-Najjar type 1 syndrome (CN1) is to lower the level of unconjugated bilirubin in their bodies. This can be achieved through treatments like phototherapy or plasmapheresis. Liver transplantation is also an option and can ultimately cure the condition.
Phototherapy, which requires intense and often daily light treatment, is a default step to treat CN1. It is particularly effective for newborns with high bilirubin levels. This therapy is more effective than traditional methods because it gives quicker results, reduces treatment time, and lessens the probability of complications. However, phototherapy tends to be less effective in older children and adults due to their thicker skin, larger bodies in comparison to their skin surface, and increased skin pigmentation.
Plasmapheresis is an optimal way to remove excess unconjugated bilirubin from the blood when the levels are extremely high. This involves taking the blood from the patient, separating the plasma from the blood cells, and replacing it with plasma from a donor. The reconstituted blood is then transfused back to the patient. As bilirubin strongly adheres to a protein called albumin, removing the albumin through plasmapheresis can greatly reduce bilirubin levels.
Medications like Orlistat, a drug used to treat obesity, and supplements such as calcium phosphate can also help lower bilirubin levels. Orlistat, which is often used in combination with calcium phosphate, helps in the excretion of unconjugated bilirubin in the intestine that matches the fat content expelled in stools. A study of patients with CN1 showed an 18% reduction in serum bilirubin levels when supplemented with calcium phosphate.
In severe cases where bilirubin levels cannot be controlled by other treatments, a liver transplant remains the only permanent solution. It works because the transplanted liver is capable of effectively breaking down bilirubin. Doctors often recommend a liver transplant to avoid the development of kernicterus, a type of brain damage.
An alternative to liver transplant, hepatocyte transplantation, offers a temporary solution. This method involves injecting healthy liver cells into the patient’s body, which reduces bilirubin levels in the short term.
Scientists are also exploring gene therapy, which involves introducing a normal version of the defective gene into the patient’s liver cells, as a potential cure for CN1.
Treatments that inhibit bilirubin production are also available; a single dose of inhibitors like tin-protoporphyrin or tin-mesoporphyrin can reduce bilirubin levels by 76% in neonates, removing the need for phototherapy. However, in adults, this treatment’s effect is temporary and only used in emergency cases.
In some cases, using phenobarbitol, a medication often used to treat seizures, can help induce the remaining functional activity of the enzyme that processes bilirubin. However, it is not effective in CN1 and is typically only used in Crigler-Najjar type 2 syndrome (CN2), where it can reduce bilirubin levels by 25%.
What else can Crigler-Najjar Syndrome be?
Determining whether a person has Crigler-Najjar syndrome (a rare condition that affects the metabolism of a substance called bilirubin) or another illness with similar symptoms depends on looking at their bilirubin levels and how long they’ve had high bilirubin levels. It’s important to consider the person’s individual health history and conditions in making a diagnosis.
Conditions that result in the body making too much bilirubin include:
- Hemolysis: Conditions such as sickle cell disease, certain types of hereditary anemia, and Rh disease in newborns can lead to hemolysis, a process where red blood cells break down. In newborns, this typically results in bilirubin levels below 6 to 8 mg/dL.
- Ineffective red blood cell production: Illnesses that interfere with the body’s ability to produce red blood cells, such as thalassemia, certain kinds of anemia, and lead poisoning, can cause very high bilirubin levels.
- Gastrointestinal (GI) bleeding and hematoma: GI bleeding and hematomas can also contribute to high bilirubin levels.
Conditions that can result from the body not getting rid of bilirubin effectively include:
- Liver disease: Any liver disease can result in jaundice (yellowing of the skin and eyes) because the liver is unable to get rid of the bilirubin in the body effectively.
- Drug-induced liver injury: Certain medications can damage the liver and make it less able to remove bilirubin from the body, causing jaundice.
There are also certain genetic conditions that can impact bilirubin levels:
- Gilbert syndrome: A relatively common genetic condition that results in benign increases in bilirubin levels.
- Lucey-Driscoll syndrome: A temporary increase in bilirubin levels in newborns, caused by substances in the mother’s and baby’s bloodstream that interfere with the breakdown of bilirubin.
Bilirubin levels can also be impacted by other special cases:
- Breast milk jaundice: A condition in some breastfed newborns where bilirubin levels increase within 2 weeks of birth and can last for 3 to 12 weeks.
- Neonatal jaundice and prematurity: Newborns can have high bilirubin levels due to factors like liver dysfunction, infection, hypothyroidism and metabolic disorders. Premature babies often have higher bilirubin levels because their livers are not as mature. Normal newborn jaundice usually goes away after about 10 days.
- Rotor syndrome and Dubin-Johnson syndrome: Rare genetic disorders that result in jaundice with high levels of bilirubin in the bloodstream.
What to expect with Crigler-Najjar Syndrome
CN1 is known to have a poor outlook, often requiring urgent medical intervention during episodes of hyperbilirubinemia. Once kernicterus, a severe condition involving the brain, occurs, it tends to be irreversible or permanent. On the other hand, CN2 has existing UGT enzyme activity, so it usually has less severe symptoms or may even occur without any noticeable symptoms. Research shows that the chances of enduring neurological damage in people with CN1 varies greatly, with up to 30% of cases resulting in lasting damage.
Possible Complications When Diagnosed with Crigler-Najjar Syndrome
Crigler-Najjar syndrome is a condition that can lead to several complications:
- Kernicterus: This happens when a fat-soluble substance called unconjugated bilirubin gets into cell membranes. If a person’s blood levels of this substance get too high, typically above 25 mg/dL, it can cross into the brain and cause damage. This risk is higher for people with severe forms of Crigler-Najjar syndrome—sometimes the levels can rise to 40 mg/dL. Parts of the brain like the hippocampus, geniculate bodies, basal ganglia, and nerve nuclei can be affected by this. It’s really important to diagnose and treat the condition early to prevent this brain damage.
- Chronic jaundice: This is continual yellowing of the skin and eyes due to high bilirubin levels. It can happen if the disease is persistent and not diagnosed early. Over time, the increasing bilirubin levels can spread throughout the body.
- Cholelithiasis: This is the formation of gallstones, caused by increased unconjugated bilirubin concentration. It usually happens later in life as bilirubin accumulates slowly.
- Liver cirrhosis: This is a condition where healthy liver tissue gets replaced by scar tissue over a long period. Children born with Crigler-Najjar syndrome usually have healthy livers at first. The exact cause of cirrhosis is unclear, but it could be due to long-term blockage of the bile duct because of gallstones, harmful effects of medication processed in the liver, side effects from phototherapy, and substances produced when the body breaks down heme.
Preventing Crigler-Najjar Syndrome
Crigler-Najjar syndrome is a condition that leads to a build-up of bilirubin in the blood. This happens due to a faulty gene that is passed down within families. The condition has two types, and their severity can vary, so it’s important to distinguish between them for the best possible treatment. It’s also wise to check other close family members for this disease. An important part of managing this condition is educating the patient’s family. This information should be easily understood by the parents and cover all aspects of the disease, including its signs and symptoms. This knowledge enables parents to detect the disease early, which can help prevent complications and improve the patient’s health outcomes. Moreover, parents should also be educated about the pros and cons of different tests and treatments, so they can make the best-informed decisions regarding their child’s health.
