Alagille Syndrome

Alagille syndrome is an autosomal dominant multisystem disorder with bile duct paucity, chronic cholestasis and cardiac, skeletal, ocular and facial abnormalities. It is caused by mutations in JAG1 (over 90%) or NOTCH2 of Notch signalling.

The incidence is about 1 in 30,000 live births. Penetrance is high but variable, and many parents are mildly affected. Long term native liver survival is about 40% to 50% by age 18 years, and the main causes of death are cardiac disease and liver failure.

Pathophysiology.

Reduced Notch signalling impairs the development of interlobular bile ducts and other organs, leading to cholestasis and fibrosis.

Neonatal cholestasis, itching, xanthomas, poor growth and characteristic facies (broad forehead, deep set eyes, pointed chin). Peripheral pulmonary stenosis and other cardiac lesions, butterfly vertebrae, posterior embryotoxon, renal and vascular anomalies, and intracranial bleeding occur.

Red flags.

• Intracranial haemorrhage or sudden severe headache.
• Severe cardiac lesion such as tetralogy of Fallot.
• Intractable itch.
• Fractures.

Cholestasis with raised bile acids, cholesterol and gamma glutamyl transferase. Liver biopsy shows paucity of interlobular bile ducts. Clinical criteria include bile duct paucity and 3 of 5 features (cholestasis, cardiac, skeletal, eye, facies). Genetic testing for JAG1 and NOTCH2 confirms. Echocardiography, spinal radiograph, slit lamp, renal ultrasound and vascular imaging (MR angiography) assess other organs.

Differential diagnosis.

• Biliary atresia.
• Progressive familial intrahepatic cholestasis.
• Alpha-1 antitrypsin deficiency.
• Infantile cholestasis from other genetic causes.

Manage itching, nutrition and vitamin deficiency, and monitor for complications. Avoid the Kasai procedure, as it worsens outcome. Liver transplant is for synthetic failure, portal hypertension, intractable itch or bone disease, but cardiac and vascular risk needs prior assessment.

• Ursodeoxycholic acid: 20 to 30 mg/kg orally daily in two divided doses; maximum 30 mg/kg daily; monitor liver tests; reduce if diarrhoea occurs.
• Maralixibat: 190 micrograms/kg orally once daily in the morning before a meal for 1 week, then 380 micrograms/kg once daily; maximum 28.5 mg daily; monitor diarrhoea, liver tests, vitamins and bile acids; reduce for diarrhoea and avoid in decompensated cirrhosis.
• Rifampicin: 10 mg/kg orally daily in two divided doses; maximum 600 mg daily; monitor liver tests and drug interactions.
• Phytomenadione: 2.5 to 5 mg orally daily; maximum 10 mg daily; monitor INR.
• Cholecalciferol and vitamin A and E replacement are adjusted to serum levels.

Monitoring. Growth, liver tests, vitamin levels and INR every 3 to 6 months; cardiology review yearly; one MR angiography of the brain at diagnosis for symptoms.

Referral and escalation. Paediatric hepatology, cardiology and transplant centre.

Special groups. Children need weight based dosing; avoid contact sports with a risk of head injury.