What is Alagille Syndrome?

Alagille syndrome is an inherited condition that causes a lower than normal number of small bile ducts inside the liver.

Normal bile duct system

Bile ducts are also known as hepatic ducts. These are tubes that carry bile from the liver cells to the gallbladder from where the bile is drained off into the intestines.

Bile is produced in the liver by the degradation of the red blood cells and has two major functions – to remove toxins and wastes away from the body and to help in digestion of fats and the fat-soluble vitamins A, D, E, and K.

What happens in Alagile syndrome?

In Alagile syndrome there are a decreased number of hepatic ducts that leads to accumulation of bile in the liver. Eventually the liver may stop working and this may necessitate a liver transplant.

As bile builds up in the liver causing damage, other organs may also be affected. This includes heart, kidneys, blood vessels, bones and eyes.

Epidemiology

Alagile syndrome occurs in about one in every 70,000 births and is seen at equal rates in both males and females. The symptoms appear before the baby completes two years.

Causes of Alagile syndrome

Alagille syndrome is inherited as an autosomal dominant trait. This means it can be inherited from one parent who has the disorder. Children who have one parent with the disorder are 50 percent likely to develop the disorder.

Those with the disorder have a genetic mutation in the Jagged1 (JAG1) gene. Mutations in the NOTCH2 gene may also be seen in less than 1% sufferers.

Symptoms of Alagille syndrome

The symptoms of Alagille syndrome vary according to the severity of the condition. They may vary between sufferers in the same family as well.

Babies with Alagille syndrome may manifest liver symptoms within the first few weeks of life. These symptoms can also occur in children and adults with the condition. The liver symptoms include:-

• Jaundice – due to accumulation of the yellowish green bilirubin in the bile in the body jaundice is seen. Jaundice occurs when the bilirubin content in the blood rises. This leads to yellowing of the skin, nail beds and whites of the eyes. Urine becomes dark in color and stools may become pale, chalky or white from a lack of bilirubin in the intestines. Mild jaundice that begins on the second or third day after birth is called physiological jaundice. This is normal and usually disappears by the second or third week of life. The jaundice of Alagille syndrome remains or persists beyond this time.

• Itching – due to rise of bilirubin levels in blood there may be itching. This usually begins after 3 months of age and can be severe
• Growth retardation and malnutrition – there may be diarrhea and the intestines fail to absorb fats and fat-soluble vitamins. This hampers growth in the baby leading to failure to thrive in infants, poor growth and delayed puberty in older children. There may be delays in learning, brittle and easily fractured bones, eye problems, blood clotting problems etc.
• Fatty deposits or xanthomas – these appear as yellow lesions or patches over skin and are caused by abnormally high cholesterol levels in the blood. Xanthomas can be found over knees, elbows, hands, and around the eyes.
• Heart defects – a heart murmur can be detected by doctors in patients with Alagille syndrome. This is due to narrowing of the pulmonary arteries, which carry blood from the heart to the lungs. 
• Eye defects - posterior embryotoxon may be seen in these patients. On examination of the eyes an opaque ring is seen in the cornea. This usually does not affect vision.
• Bone deformities
• Kidney disorders – there are several kidney disorders seen in patients of Alagille syndrome. These range from small kidneys to cysts and kidneys that have decreased functions.
• Facial features – children with Alagille syndrome may have a typical facial feature of deep-set eyes, straight nose, small, pointed chin, wide forehead etc.
• Spleen enlargement – as the blood from spleen normally drains in the liver, a blockage in the liver leads to portal hypertension. This causes the spleen to enlarge in later stages. An enlarged spleen is likely to be ruptured on impact over the abdomen.
• Blood vessel abnormalities – there is a high risk of internal bleeding or stroke due to these abnormalities.

Diagnosis of Alagille syndrome

Because of its rare incidence and varying symptoms, it may be difficult to diagnose Alagille syndrome. Laboratory tests including blood   tests to check  liver function and nutritional status are prescribed first. Usually high levels of bilirubin are detected.

An abdominal ultrasound is performed to detect liver enlargement and state of the bile ducts. To confirm the condition a liver biopsy is advised. This checks the decreased number of hepatic ducts.

Other organ systems are also evaluated. This includes checking the heart, eyes, kidneys etc. An X ray of the spine is performed to check for deformities.

Genetic tests may be advised to confirm the diagnosis. The JAG1 gene mutation alone may be diagnostic of the condition. If there are no symptoms along with the mutation, the person may be refereed for genetic counselling.

Treatment of Alagille syndrome

Treatment of Alagille syndrome aims at increasing the flow of bile from the liver thereby allowing normal growth and development to return.

Ursodiol is the only drug approved by the U.S. Food and Drug Administration to increase bile flow. Excessive itching is resolved as the bile flow improves. To relieve itching medications like cholestyramine, rifampin, naltrexone or antihistamines may be prescribed. Skin needs to be kept moisturized and hydrated.

Surgery is the next step. Partial external biliary diversion (PEBD) may provide better flow of bile and relieve itching. PEBD connects one end of the small intestine to the gallbladder and the other end to an opening in the abdomen by creating an artificial opening called stoma that allows bile to leave the body and get collected in a pouch. In severe cases of liver failure a liver transplant may be necessary.

Prognosis for patients with Alagille syndrome

The outlook or prognosis for people with Alagille syndrome depends on the severity of liver damage and associated problems.

Fifteen percent of people with Alagille syndrome will eventually require a liver transplant.

According to evidence around 75% of children diagnosed with Alagille syndrome live to at least 20 years of age with early nutritional, medical and surgical management.

Many adults with Alagille syndrome who improve with treatment lead normal, productive lives. Death is mainly caused by liver failure, heart problems and associated conditions.