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Liver Disorders and Diseases

Alagille Syndrome

What is Alagille Syndrome?

Alagille syndrome is an inherited disorder in which a person has fewer than the normal number of small bile ducts inside the liver. Bile ducts, also called hepatic ducts, are tubes that carry bile from the liver cells to the gallbladder and eventually drain into the small intestine. Bile is a liquid produced in the liver that serves two main functions: carrying toxins and waste products out of the body and helping the digestion of fats and the fat-soluble vitamins A, D, E, and K. The decreased number of hepatic ducts causes bile to build up in the liver, leading to liver damage. Eventually the liver may stop working and a liver transplant is necessary.

A child who has a parent with Alagille syndrome has a 50 percent chance of developing the disorder. Most people with Alagille syndrome have a mutation, or defect, in the Jagged1 (JAG1) gene. Mutations in the NOTCH2 gene are seen in less than 1 percent of people with Alagille syndrome.

Symptoms

The symptoms of Alagille syndrome and their severity vary, even among people in the same family.

Infants with Alagille syndrome may have symptoms of liver disease and poor bile drainage from the liver in the first few weeks of life. These symptoms can also occur in children and adults with Alagille syndrome.

  • Jaundice. Many healthy newborns have mild jaundice due to immaturity of the liver. This type of jaundice disappears by the second or third week of life, whereas the jaundice of Alagille syndrome remains. Infants with jaundice that persists should be checked by a doctor.
  • Pruritus. The buildup of bilirubin in the blood may cause itching, also called pruritus. Pruritus usually starts after 3 months of age and can be severe.
  • Malabsorption and growth problems. People with Alagille syndrome may have diarrhea because of malabsorption, a condition in which the bowel does not properly absorb fats and fat-soluble vitamins. People with Alagille syndrome and malabsorption may develop bone fractures, eye problems, blood-clotting problems, and learning delays.
  • Xanthomas. Xanthomas are fatty deposits that appear as yellow bumps on the skin. They are caused by abnormally high cholesterol levels in the blood, which is common in people with liver disease. Xanthomas are found on the abdomen, knees, elbows, hands, and around the eyes and are harmless.

Alagille syndrome can affect other parts of the body in ways that may help doctors distinguish it from other liver conditions.

  • Heart. A heart murmur is the most common sign of Alagille syndrome other than liver disease. Most people with Alagille syndrome have a narrowing of the pulmonary arteries, which carry blood from the heart to the lungs. This narrowing causes a murmur that can be heard with a stethoscope, but usually it does not cause problems. A small number of people with Alagille syndrome have more serious heart conditions involving problems with the walls or the valves in the heart. The more serious conditions may require medications and corrective surgery.
  • Face. Many children with Alagille syndrome have deep-set eyes; a straight nose; a small, pointed chin; and a prominent, wide forehead. These features are not usually recognized until after infancy. The face typically changes with age, and by adulthood the chin is more prominent.
  • Eyes. Posterior embryotoxon is a condition in which an opaque ring is seen in the cornea, the transparent covering of the eyeball. A specialist performs an eye examination, called the slit lamp test, to look for the condition. The abnormality is common in people with Alagille syndrome and usually does not affect vision.
  • Skeleton. The shape of the bones of the spine may look abnormal on an x ray, but this abnormality rarely causes spine problems.
  • Kidneys. A wide range of kidney diseases can occur in Alagille syndrome. Some people have small kidneys or cysts in the kidneys. The kidneys can also have decreased function.
  • Spleen. Blood flow from the spleen drains directly into the liver. When liver disease is advanced, the blood flow backs up into the spleen and other blood vessels. This condition is called portal hypertension. The spleen may enlarge in the later stages of liver disease.
  • Blood vessels. People with Alagille syndrome may have abnormalities of the blood vessels in the head and neck. This serious complication can lead to internal bleeding or stroke. If a person with Alagille syndrome suffers a head injury, prompt evaluation and magnetic resonance imaging (MRI) or a computerized tomography (CT) scan of the brain are needed to check for problems. Alagille syndrome can also cause narrowing or bulging of other blood vessels in the body.

Diagnosis

Because the symptoms of Alagille syndrome vary and because the syndrome is so rare, the disorder can be difficult to diagnose. The doctor will perform a thorough physical examination to look for clinical symptoms of the disorder. If Alagille syndrome is suspected, the doctor will order one or more of the following tests and examinations:

  • blood tests to check liver function and nutritional status
  • an abdominal ultrasound to look for liver enlargement and to rule out other conditions
  • a liver biopsy to check for a decreased number of hepatic ducts
  • a cardiology examination to check for heart problems
  • an eye examination to check for posterior embryotoxon
  • an x ray of the spine to look for abnormalities
  • examinations of the blood vessels and kidneys to check for abnormalities

To make a diagnosis of Alagille syndrome, a positive liver biopsy and the presence of three of the following symptoms are usually required:

  • liver symptoms
  • heart abnormalities or murmurs
  • skeletal abnormalities
  • posterior embryotoxon
  • facial features typical of Alagille syndrome

Treatment

Treatment of Alagille syndrome focuses on trying to increase the flow of bile from the liver, maintaining the child’s normal growth and development pattern, and correcting any of the nutritional deficiencies that often develop. Because bile flow from the liver to the intestine is slowed in Alagille syndrome patients, medications designed to increase the flow of bile are frequently prescribed. While reduced bile flow into the intestine leads to poor digestion of dietary fat, a specific type of fat can still be well digested, and therefore infant formulas containing high levels of medium-chain triglycerides (MCT) are usually substituted for conventional formulas. Some infants can grow adequately on breast milk if additional MCT oil is given. There are no other dietary restrictions.

Problems with fat digestion and absorption may lead to deficiency of fat-soluble vitamins (A, D, E, and K). Deficiencies of these vitamins can be diagnosed by blood tests and can usually be corrected by large oral doses. If the child's system cannot absorb vitamins given by mouth, vitamin injections into the muscle may be necessary. Sometimes surgery is necessary during infancy to help establish the diagnosis of Alagille syndrome by direct examination of the bile duct system and through liver biopsy. However, surgical reconstruction of the bile duct system is not recommended because bile can still flow from the liver, and there is presently no procedure that can correct for the loss of the bile ducts within the liver. Occasionally, liver cirrhosis advances to a stage where the liver fails to perform its functions. Liver transplantation is then considered.

Alagille syndrome is treated in the Pediatric Liver Center at Hopkins Children's.  

External Links:

National Library of Medicine 

American Liver Foundation

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