Alagille Syndrome

Background

• First described by Daniel Alagille in 1969
• Also known as arteriohepatic dysplasia
• Caused by mutations in JAG1 (most common) or NOTCH2
• Disrupts Notch signaling pathway critical for organ development

Epidemiology

• Incidence: 1 in 30,000 to 50,000 live births
• Autosomal dominant inheritance with variable expressivity
• ~50–70% of cases are de novo mutations

Pathophysiology

• Defective Notch signaling impairs bile duct formation
• Leads to intrahepatic bile duct paucity (Near absence of intrahepatic bile ducts in the portal tracts, especially in the periphery of the liver, with preserved central ducts.) This is a hallmark of Alagille
  
• Also affects heart, skeleton, kidneys, and eyes

Clinical Manifestations

• Hepatic: Cholestasis, jaundice, pruritus, xanthomas
• Cardiac: Pulmonary artery stenosis, tetralogy of Fallot
• Facial features: Prominent forehead, deep-set eyes, pointed chin
• Skeletal: Butterfly vertebrae
• Ocular: Posterior embryotoxon (a prominent, anteriorly displaced Schwalbe’s line, which appears as a white or gray arc near the corneal periphery; the edge of the cornea where the corneal endothelium meets the trabecular meshwork. Seen on slit lamp exam)
  
• Renal: Tubulointerstitial disease
• Growth: Failure to thrive, short stature

Diagnosis

• Clinical criteria: bile duct paucity plus ≥3 of the following:
  • Cardiac defect
  • Skeletal anomaly
  • Ocular anomaly
  • Characteristic facies
  • Family history
• Confirmed by genetic testing for JAG1 or NOTCH2

Imaging

• Abdominal ultrasound: hepatomegaly or splenomegaly
• MRCP: bile duct architecture
• Echocardiogram: congenital heart defects
• Spine X-ray: butterfly vertebrae

Liver Biopsy & Histology

• Key finding: paucity of intrahepatic bile ducts in portal tracts
• May show portal fibrosis, inflammation, or cholestasis
• Central ducts may appear normal

Treatment

• Supportive care for cholestasis:
  • Ursodeoxycholic acid
  • Rifampin for pruritus
  • Fat-soluble vitamin supplementation
• Cardiac surgery if needed
• Liver transplantation for progressive liver failure or intractable pruritus
• Multisystem evaluation before transplant listing

Prognosis

• Highly variable depending on organ involvement
• Liver disease may stabilize or progress to cirrhosis
• Cardiac and renal anomalies impact long-term outcomes
• Lifelong multidisciplinary care is essential