Saanichton, BC

Dr. Miguel A. Lipka

Alagille Syndrome

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Alagille syndrome is a genetic disorder that can affect the liver, heart, and other parts of the body.

The estimated prevalence of Alagille syndrome is 1 in 70,000 people. Problems associated with Alagille syndrome generally become evident in infancy or early childhood.

Mutations in the JAG1 gene or small deletions of genetic material on chromosome 20 that include the JAG1 gene cause Alagille syndrome. A few people with Alagille syndrome have mutations in a different gene, called NOTCH2. The JAG1 and NOTCH2 genes provide instructions for making proteins that fit together to trigger interactions called Notch signaling between neighboring cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Changes in either the JAG1 gene or NOTCH2 gene probably disrupt the Notch signaling pathway. As a result, errors may occur during development, especially affecting the bile ducts, heart, spinal column, and certain facial features.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered or deleted gene in each cell is sufficient to cause the disorder. Other cases result from new mutations in the gene or new deletions of genetic material on chromosome 20 that occur as random events during the formation of reproductive cells (eggs or sperm) or in early fetal development. These cases occur in people with no history of the disorder in their family.

The severity of the disorder varies among affected individuals, even within the same family. Symptoms range from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation.

One of the major features of Alagille syndrome is liver damage caused by abnormalities in the bile ducts. These ducts carry bile (which helps to digest fats) from the liver to the gallbladder and small intestine. In Alagille syndrome, the bile ducts may be narrow, malformed, and reduced in number (bile duct paucity). As a result, bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream. Signs and symptoms arising from liver damage in Alagille syndrome may include:

  • A yellowish tinge in the skin and the whites of the eyes (jaundice)
  • Itchy skin
  • Deposits of cholesterol in the skin (xanthomas)

Alagille syndrome is also associated with several heart problems, including impaired blood flow from the heart into the lungs (pulmonic stenosis). Pulmonic stenosis may occur along with a hole between the two lower chambers of the heart (ventricular septal defect) and other heart abnormalities. This combination of heart defects is called Tetralogy of Fallot.

People with Alagille syndrome may have distinctive facial features including:

  • A broad, prominent forehead
  • Deep-set eyes
  • A small, pointed chin

The disorder may also affect the blood vessels within the brain and spinal cord and the kidneys. Affected individuals may have an unusual butterfly shape of the bones of the spinal column that can be seen in an X-ray.

Prognosis depends on the severity of the bile flow obstruction and scarring of the liver, and the severity of other problems that may develop -- such as heart or lung problems or problems related to poor nutrition.

A typical course of liver disease with Alagille syndrome patients is worsening cholestasis (decreasing bile flow) for several years, and then some improvement after that time. Children with Alagille syndrome generally have a better outcome than children with other liver disorders at the same age. Many adults with alagille syndrome lead normal lives.

There is no known cure for Alagille syndrome. Most of the treatments available are aimed at preventing complications, increasing the flow of bile from the liver, maintaining normal growth and development and reducing blood cholesterol levels.

  • Medications. Medicine may be used to increase bile flow and to relieve severe itching caused by buildup of bile in the blood and skin. These same medicines may be used to treat high cholesterol levels that cause the hard, whitish nodules that develop in the skin in Alagille syndrome patients.

  • Vitamin supplements. Reduced bile flow can lead to difficulty digesting fat and vitamins from a child's diet. Fat-soluble vitamin supplements (A, D, E, and K) may be used.

  • Baby formula rich in triglyceride. Baby formula rich in a type of fat that can be digested despite reduced bile flow may be used to help with fat absorption in infants.

  • High-calorie diet. Alagille syndrome patients often have difficulty absorbing the calories they eat. To prevent malnutrition and growth failure, a high-calorie diet with a lot of protein may be recommended. A feeding tube that delivers large quantities of nutrients overnight may be used.

  • Liver transplantation. A small percentage of patients will develop cirrhosis (severe damage to the liver). Liver transplantation is the only option for these patients.

    A liver transplant also may be the last resort for patients with severe itching, portal hypertension (high blood pressure) and severe growth failure that is not responding to medication. Liver transplantation has been used successfully in these cases.