Alagille Syndrome

Alagille syndrome is a rare, inherited disorder in which bile flow from the liver is decreased and the there are fewer than normal bile ducts.

Alagille syndrome is a disorder that often affects the liver and other organs, including the heart, eyes, spine and kidneys.

Often, patients with alagille syndrome have distinctive facial appearances. A small number of patients (about 15%) go on to develop severe liver disease and require liver transplantation.

This disorder is usually present at birth. Alagille syndrome is one of the most common inherited disorders that causes reduced bile flow within the liver. It occurs about once in every 100,000 births.

What are the causes of alagille syndrome?

Recent studies have discovered that defects of a specific gene cause alagille syndrome. The disease usually is inherited from one parent.

A single copy of the diseased gene (received from either the mother or father) "dominates" the other normal gene and results in this disease.

There is a 50% chance a parent with alagille syndrome will transmit this disorder to their child. Family members with Alagille syndrome may be affected very differently by the disorder.

Bile is produced in the liver and then travels through the many small bile ducts in the liver into one large bile duct, and eventually into the intestines. In patients with alagille syndrome, the lack of small bile ducts inside the liver slows down the flow of bile from the liver to the intestines.

Bile is composed of bilirubin, bile salts, cholesterol and metals such as copper. Bile acids are necessary to absorb fat and certain vitamins. When the bile flow is decreased, each of its components builds up in the body, and the body is not able to properly absorb fat and vitamins. This causes a wide range of symptoms.

What are the signs and symptoms of alagille syndrome?

Symptoms of alagille syndrome range from mild to severe. Symptoms within the first three months of life often include:

• Jaundice, usually present at birth (yellowing of the skin)
• Severe itching (caused by the buildup of bile salt in the body)
• Pale, loose or clay-colored stools (this happens because there is little or no bile reaching the intestine to color the bowel movements)
• Poor weight gain (due to a lack of bile needed to digest and absorb fat)
• Poor growth
• Deficiency of vitamins A, D, E and K which depends on bile acids for absorption; this may result in vision changes, rickets, difficulty with balance and poor clotting of the blood
• Heart murmurs, due to narrowing of the blood vessels in the lung (peripheral pulmonary artery stenosis)

Other symptoms that may develop later include:

• Jaundice that will not go away
• Continued growth and development problems in early childhood
• Enlarged liver (feels larger and harder than normal)
• Hard, whitish nodules (called xanthonmas) that develop in the skin due to cholesterol and fatty deposits; the nodules usually occur in spots of repeated trauma in young children, such as knees and elbows
• Urine appears very dark yellow or brown (due to high levels of bilirubin in the bloodstream which pass to the kidneys)
• Persistent itching

How is alagille syndrome diagnosed?

A diagnosis of alagille syndrome is made based on either tests or a physical examination. While there are specific findings that indicate alagille syndrome, all patients do not demonstrate all of them.

Reduced bile flow is one finding that indicates alagille symdrome. Symptoms of reduced bile flow include jaundice, itching and cholesterol deposits in the skin.

A liver biopsy may be done to show examine the bile ducts and degree of scarring in the liver. Liver function tests are blood tests used to assess the general state of the liver or biliary system.

A nuclear scan may be done to show how much bile is flowing from the liver. Genetic testing may be available through research laboratoraties but as of 2006, it is not routinely available.

Other findings that may indicate alagille syndrome include:

• Heart murmur (due to narrowing of the blood vessel connecting the heart to the lungs)
• Bone defects (shape of the bones in the spinal column may look like a butterfly's wings)
• Kidney problems or kidney failure
• Distinct physical features, such as a broad forehead, straight nose, deep set eyes, a small, pointed chin, and fingers that are shorter than normal
• Problems with the eye -- an extra thickening of a line, known as the Schwalbe's line on the surface of the eye

What is the treatment?

There is no cure for alagille syndrome. Management of the disorder is 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.

What is the long-term prognosis for alagille syndrome patients?

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