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What is Alagille Syndrome and How is it Diagnosed?

Alagille syndrome (AGLS) is a genetic disorder of the liver that develops when bile ducts do not form properly or there are too few of them. Bile ducts are small tubes that allow bile, a digestive enzyme, to pass through to the small intestine. When bile cannot flow freely, it backs up into the liver, a condition called cholestasis that can lead to liver damage.

AGLS is caused by mutation of a gene. In most cases it is the Jagged1 gene, but in less than 1% of cases it is the Notch2 gene. It is an autosomal dominant genetic defect, which means that it can be passed down to a child from just one parent with the gene defect. AGLS can show up with different symptoms in different people, even in the same family. As the authors of a study published in the journal Diagnostics explain:

“[AGLS] is a complex disease with significant inter and intrafamilial variable expression that poses significant diagnostic challenges and requires high index of suspicion for diagnosis.”

Often the first symptom that anything is wrong is jaundice, or yellowing of the skin and whites of the eyes. Dark urine or pale stools, pruritus (itching), and fatty deposits on the skin called xanthomas are also indicators of problems with the liver. If the doctor suspects a liver problem, including AGLS, they will go through a series of steps including a medical history, physical exam, and running one or more tests. AGLS can cause problems with other organ systems including the heart, eyes, skeleton, and kidneys, so a doctor will look for symptoms throughout the body.

The doctor will make a determination of AGLS if someone has positive indicators of the disease in three or more of the following areas:

  • liver
  • heart
  • eyes
  • facial structure
  • skeleton
  • blood vessels
  • kidneys

Or, they will make a determination of AGLS if there is a family member with the disorder and two positive indicators from the list above.

Up to 96% of children born with AGLS have uniquely identifiable facial features including a broad, prominent forehead, wide-set, deep eyes, and small and pointed chin. These are often a first sign of the disease to the attending doctor. They may also have a unique feature inside their eye that will not affect vision but can be viewed by a doctor during a slit-lamp exam.

People with AGLS often have unusually butterfly-shaped vertebra in their spinal column. The doctor may order x-rays to view the spine. They may also order tests on the heart to check for certain defects associated with the syndrome. The doctor may order a liver biopsy to take a piece of liver tissue and check for signs of liver disease. This is often a needle biopsy and can be done as an outpatient procedure.

Genetic testing will usually be ordered to check for mutations in the genes that cause AGLS. Specifically, these are the Jagged1 gene and the Notch2 gene. To do these tests blood or saliva are collected and sent to specialized labs for analysis. Your doctor may need to refer you to a geneticist to have this testing done.

Imaging tests may be ordered to check for problems throughout the body. These could include:

  • ultrasound
  • magnetic resonance imaging (MRI)
  • cholangiography – an x-ray of the bile ducts
  • hepatobiliary scan – an image of the bile ducts using a small amount of radioactive material
  • x-ray
  • echocardiogram of the heart
  • magnetic resonance angiography – an MRI that checks for blood vessel problems

AGLS is rare, affecting only an estimated 1 in 70,000 babies. In her personal story, Mighty contributor Mia Carella explains what it is like navigating healthcare with a child who has AGLS.

“Because Alagille syndrome is so rare, we often get questions from doctors. The thorough and interested doctors often inform us that they will “read up” on it after our appointment. […] Things have improved over the years, and as knowledge about Alagille syndrome and awareness grows, things will continue to get easier.”

There is no cure for AGLS so treatment focuses on symptoms and lifestyle management. Several medications are available to assist with symptoms, depending on which organ system they impact. Itching, called pruritus, is often one of the worst symptoms and can be treated with medication and home care. The UK-based charity Children’s Liver Disease Foundation has a list of helpful tips for relieving itching on their website.

If you’ve had an experience with Alagille syndrome or the diagnosis process let us know about it in the comments below!