Alagille syndrome

Alagille syndrome
ICD-10	Q44.7 (EUROCAT Q44.71)
ICD-9	759.89
OMIM	118450
DiseasesDB	29085
MeSH	D016738

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Overview

Alagille syndrome is a multisystem genetic disorder that affects the liver, heart, eyes, face, skeleton, kidneys and vascular system. Problems associated with the disorder generally become evident in infancy or early childhood. The patients have a characteristic facial appearance. The disorder is inherited in an autosomal dominant pattern, and the estimated prevalence of Alagille syndrome is 1 in every 70,000 live births. The clinical features are highly variable even within the family.

Pathophysiology

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.

Mutations in the JAG1 gene cause Alagille 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 disrupt the signaling pathway, causing errors in development, especially of the heart, bile ducts in the liver, spinal column, and certain facial features.

NOTCH2 is 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.

Children with Alagille syndrome may be at risk for pathologic fractures, which manifest at an early age and in a unique distribution favoring the lower extremity long bones .

Associated Conditions

Alagille syndrome can be associated with congenital heart disease, particularly Tetralogy of Fallot. The kidneys and central nervous system may also be affected.

Diagnosis

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. The major clinical feature is due to cholestasis, due to bile duct paucity as seen on liver biopsy. Congenital heart defect, mostly pulmonary stenosis, typical facial features, butterfly vertebrae and posterior embryotoxon in the eye are commonly found. Renal and central nervous system abnormalities may occur.

Symptoms

• Itching

Physical Examination

Head, Eyes, Ears, Nose, Throat

• A broad, prominent forehead, deep-set eyes, and a small pointed chin may be present.
• Scleral icterus

Skin

• Jaundice
• Xanthomas

Laboratory Studies

Biochemical Evaluation

Total Bilirubin >6.5 mg/dL, Conjugated Bilirubin >4.5 mg/dL, and cholesterol >520 mg/dL in children younger than 5 years of age are likely be associated with severe liver disease in later life .

Liver Biopsy

A liver biopsy may indicate too few bile ducts (bile duct paucity).

X ray

An unusual butterfly shape of the bones of the spinal column that can be seen in an x-ray

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 function.

Medical Therapy

The medical management of Alagille Syndrome is complex and continues to generate controversy. The significant variability of organ involvement requires the managing physician to have an understanding of the breadth and interplay of the variable manifestations. Furthermore, the liver disease in particular requires an appreciation of the natural history and evolution of the profound cholestasis.

Several medications are used to improve bile flow and reduce itching (pruritus): Ursodiol (Actigall), Hydroxyzine (Atarax), Cholestyramine, Rifampicin, and Phenobarbitol have all been used to varying degrees of success.

Many patients with Alagille's Syndrome will also benefit from a high dose of a multivitamin such as ADEK (contining 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 Allagile Syndrome. Also, because the pulmonary arteries are often narrow in Alagille patients, a catheterization process similar to angioplasty may be used to widen the arteries to reduce pressure on the heart's pumping valves. 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. However, liver transplantation from donor parents should always be preceded by genetic testing because cases have been known where donor mother was also found to have alagille syndrome post transplant owing to the autosomal dominant inheritance pattern of the syndrome. Death from graft failure, neurological, and cardiac complications is significantly higher in patients with Alagille Syndrome than patients with Biliary Atresia .

Recently, a procedure called partial biliary diversion has been used to significantly reduce pruritus, jaundice, and xanthomas caused by poor bile flow. 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.

The Kasai procedure, although appropriate for children with biliary atresia, does not benefit children with Alagille Syndrome and actually appears to worsen outcome .

Prognosis

Mortality is approximately 10%, with vascular accidents, cardiac disease, and liver disease accounting for most of the deaths.

See also

• Progressive familial intrahepatic cholestasis

External links

• Alagille Syndrome, Liver Diseases and Treatments, Cincinnati Children's Hospital Medical Center

Support groups

• Alagille Syndrome Alliance

• LIVER FAMILIES: An online support group for families whose lives have been touched by pediatric liver disease and transplant.

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