Alagille Syndrome- Gastroenterology, Medical Genetics

Alagille syndrome, also termed arteriohepatic dysplasia, is a disorder related to the bile ducts. It is due to a mutation of the NOTCH2 and JAG1 genes, resulting in too few bile ducts forming during development. This means bile cannot drain out of the liver properly, leading to excess bile in the body, resulting in multiple problems, including liver damage, kidney damage, heart problems, skin and eye issues, and bone problems. Liver failure occurs in 15% of patients, which is why rapid diagnosis and treatment are important. Alagille syndrome cannot be cured but needs to be managed.

Who treats Alagille syndrome?

A hepatologist is involved in treating Alagille syndrome. A hepatologist is a doctor who specializes in diseases of the liver, bile ducts, pancreas, and gallbladder. Cardiologists and nephrologists may also be consulted if the patient has heart or kidney-related issues. In addition, genetics counselors are often consulted because the mutation is inherited in 50% of cases.

Diagnosing Alagille Syndrome

Alagille syndrome is often diagnosed in infancy, further to which a treatment plan is formulated.

The diagnostic process can involve the procedures described below.

• Blood tests can detect cholestasis as indicated by alkaline phosphatase and γ-glutamyl transpeptidase being at very high levels.
• Endoscopic retrograde cholangiopancreatography (ERCP): A test to examine the bile ducts and biliary tree.
• Hepatobiliary iminodiacetic acid (HIDA) scan: Imaging method that uses a radioactive tracer to highlight the bile ducts in the liver.
• Liver biopsy: A small piece of tissue is taken and examined microscopically. With Alagille syndrome, only a few bile ducts will be seen in a section of liver tissue.
• Genetic tests for the JAG1 and NOTCH2 mutations.
• Physical signs such as a white outer ring around the cornea, large forehead, bulbous nose, and pointed chin, and symptoms such as jaundice and itchy skin.
• MRI, CT, and X-ray imaging showing butterfly-shaped vertebrae and anomalies in the liver.
• An echocardiogram showing heart abnormalities.

Treatment options for Alagille syndrome

Vitamin supplements and dietary changes

Patients with Alagille syndrome cannot easily absorb the fat-soluble vitamins of A, K, D, and E. This is why nutrient supplements may be needed.

A special infant formula may be used. In general, patients with Alagille syndrome need to follow a diet that is high in calories and includes carbohydrates with medium-chain triglycerides (MCTs). The carbohydrates and MCTs are easy to digest.

Check with your doctor regarding the supplements and dietary changes advised to help manage Alagille syndrome.

Skin moisturizers

Patients with Alagille syndrome may benefit from using moisturizers to ease the skin discomfort they often feel.

Medication

The following medications can help to alleviate some of the symptoms of the disease.

• Sertraline: This anti-depressant has been used to ease itching due to liver problems.
• Rifampicin: This medication is also an anti-microbial and has been used to treat itching in patients with liver disease.

• Ursodiol: This is used to help with bile flow since Alagille syndrome results in cholestasis (slow bile flow).
• Cholestyramine: This medicine binds with bile in the gut to help reduce itchy skin resulting from bile buildup.
• Maralixibat: This is an ileal bile acid transporter inhibitor drug that was recently approved to help treat pruritic (itchy) skin in patients with Alagille syndrome.

Partial biliary diversion surgery

This procedure is done to change the path of bile to help decrease the reuptake of bile that causes itchy skin. This helps decrease the accumulation of bilirubin in the blood and bile salts in the skin, thereby reducing the associated irritation.

Either a partial internal biliary diversion (PIBD) or partial external biliary diversion (PEBD) can be done.

• PIBD: This involves surgically altering where the bile duct from the gallbladder attaches to the small intestine.
• PEBD: In this procedure, the gallbladder is attached to an opening in the abdomen (stoma) so that bile can drain out.

Cardiac surgery

A cardiac defect has been observed in about 9 out of 10 children born with Alagille syndrome. Some of these patients will require heart surgery to correct the problem. Patients may need surgery to correct the following cardiac issues:

• Pulmonary artery stenosis: A narrowed artery of the lungs.
• Aortic stenosis: A narrowing of the aortic valve.
• Tetralogy of Fallot: Involves four conditions of the heart, i.e., a ventricular septal defect (VSD), pulmonary stenosis, a displaced aorta, and right ventricular hypertrophy
• Atrial septal defect: A hole in the tissue separating the atria.
• Ventricular septal defect: A hole in the tissue separating the ventricles.

Liver transplant surgery

About 10% to 30% of people with Alagille syndrome will need a liver transplant. A liver transplant becomes necessary when liver failure occurs.

References:

• Ganesh, R., Suresh, N., Sathiyasekeran, M., & Ramachandran, P. (2011). Partial internal biliary diversion: a solution for intractable pruritus in progressive familial intrahepatic cholestasis type 1. Saudi Journal of Gastroenterology, 17(3), 212.
• Hwang, S. M., Jeon, T. Y., Yoo, S. Y., Kim, J. H., Kang, B., Choe, Y. H., ... & Kim, J. S. (2016). Alagille syndrome candidates for liver transplantation: differentiation from end-stage biliary atresia using preoperative CT. Plos one, 11(2), e0149681.
• Kamath, B. M., Yin, W., Miller, H., Anand, R., Rand, E. B., Alonso, E., ... & Studies of Pediatric Liver Transplantation. (2012). Outcomes of liver transplantation for patients with Alagille syndrome: the studies of pediatric liver transplantation experience. Liver transplantation, 18(8), 940-948.
• Sheflin-Findling, S., Arnon, R., Lee, S., Chu, J., Henderling, F., Kerkar, N., & Iyer, K. (2012). Partial internal biliary diversion for Alagille syndrome: case report and review of the literature. Journal of pediatric surgery, 47(7), 1453-1456.
• Shirley, M. (2022). Maralixibat: first approval. Drugs, 1-6.
• Turnpenny, P. D., & Ellard, S. (2012). Alagille syndrome: pathogenesis, diagnosis and management. European Journal of Human Genetics, 20(3), 251-257.
• https://www.niddk.nih.gov/health-information/liver-disease/alagille-syndrome/treatment

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