Alagille syndrome

Alagille syndrome is a genetic disorder that affects the liver, heart, kidney, and other systems of the body. Problems associated with the disorder generally become evident in infancy or early childhood. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 100,000 live births.

It is named for Daniel Alagille.

Presentation
The severity of the disorder can vary within the same family, with symptoms ranging from so mild as to go unnoticed to severe heart and/or liver disease requiring transplantation.

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), itching (pruritus), and deposits of cholesterol in the skin (xanthomas). A liver biopsy may indicate too few bile ducts (bile duct paucity) or, in some cases, the complete absence of bile ducts (biliary atresia). Other signs of Alagille syndrome include congenital heart problems, an unusual butterfly shape of one or more of the bones of the spinal column that can be seen in an x-ray, certain eye defects, and narrowed pulmonary arteries that can contribute to increased pressure on the right heart valves.

Tetralogy of Fallot is a heart defect common in Alagille's syndrome patients. This defect consists of four separate heart abnormalities: Pulmonary stenosis; overriding aorta; ventricular septal defect; and right ventricular hypertrophy. Untreated Tetralogy of Fallot mortality rates range from 70 percent by age 10 to 95 percent by age 40. However, complete surgical repair can significantly improve both longevity and quality of life in Allagille's patients.

Many people with Alagille syndrome have similar facial features, including a broad, prominent forehead, deep-set eyes, and a small pointed chin. The kidneys and central nervous system may also be affected.

Pathophysiology
Microdeletion of the 20p12 gene corresponding to JAG1 results in Alagille syndrome, similar to the inheritance pattern of Williams syndrome. The JAG1 gene is involved in signaling between adjacent cells during embryonic development. This signaling influences how the cells are used to build body structures in the developing embryo. Mutations in JAG1 disrupts the Notch signaling pathway, causing errors in development, especially of the heart, bile ducts in the liver, spinal column, eyes, blood vessels and certain facial features.

NOTCH2 mutations are also associated with Alagille syndrome.

Narrowed and malformed bile ducts in the liver produce many of the health problems associated with Alagille syndrome. Bile is produced in the liver and moves through the bile ducts into the small intestine, where it helps to digest fat. In Alagille syndrome, the bile builds up in the liver and causes scarring that prevents the liver from working properly to eliminate wastes from the bloodstream.

Genetics
This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene is sufficient to cause the disorder. In some cases, an affected person inherits the mutation from one affected parent. Other cases may result from new mutations in the gene. These cases occur in people with no history of the disorder in their family.

Treatment
There is no known cure for Alagille's Syndrome. Most of the treatments available are aimed at improving the functioning of the heart and reducing the effects of impaired liver, kidney, and spleen function.

Medication
Several medications are used to improve bile flow and reduce itching (pruritus): ursodiol (Actigall), hydroxyzine (Atarax), cholestyramine, rifampicin, and phenobarbital have all been used with varying degrees of success.

Many patients with Alagille's Syndrome will also benefit from a high dose of a multivitamin such as ADEK (continuing high levels of vitamins A, D, E, and K), as the reduced bile flow makes it difficult to absorb and utilize these vitamins.

Surgery
Corrective surgery is sometimes needed to repair heart defects associated with Alagille Syndrome. Also, because the pulmonary arteries are often narrow in patients with Alagille syndrome, a catheterization process similar to angioplasty may be used to widen the arteries to reduce pressure on the right side of the heart. In moderate to severe cases, stents may be placed in the arteries to increase their diameter. Transplantation of the liver has been a successful alternative to medication in severe cases.

Partial biliary diversion has been used to significantly reduce pruritus, jaundice, and xanthomas caused by poor bile flow in patients with bile duct paucity. A portion of the bile produced by the liver is directed through a surgically created stoma into a plastic pouch on the patient's lower right abdomen. The pouch is periodically drained as it fills with bile.

Patients with biliary atresia may require a Kasai procedure to improve bile drainage; however, later liver transplantation is still often necessary.