Liver & intrahepatic bile ducts

Developmental anomalies / cysts

Alagille syndrome

Topic Completed: 1 November 2016

Minor changes: 16 June 2021

Copyright: 2002-2021,, Inc.

PubMed Search: Alagille syndrome[TI] liver[TI]

Kalyani R. Patel, M.D.
Page views in 2020: 1,977
Page views in 2021 to date: 2,148
Cite this page: Patel K. Alagille syndrome. website. Accessed December 6th, 2021.
Definition / general
  • Also called arteriohepatic dysplasia
  • Represents the etiology behind syndromic paucity of bile ducts
Essential features
  • Genetic disorder with vascular, biliary and other anomalies
  • Absence of intrahepatic bile ducts with clinical severity ranging from severe neonatal cholestasis mimicking biliary atresia to childhood intermittent jaundice
  • Progression to cirrhosis is rare
  • 2 distinct genetic mechanisms:
    • Vast majority (ALGS1) are autosomal dominant, due to mutations in Jagged1 gene on chromosome 20p12, which encodes a ligand for NOTCH1 and plays a role in epithelial mesenchymal interactions (Nat Genet 1997;16:235)
      • Gene penetrance is high but expression is variable; 50 - 70% patients have new mutations
    • Second genetic abnormality (ALGS2) accounting for small proportion of cases, is related to the mutations in the gene encoding NOTCH2 on chromosome 1p13 and has more severe renal disease (Am J Hum Genet 2006;79:169)
Clinical features
  • Reported incidence is 1:30,000 of live births
  • Common clinical features: abnormal inverted triangular facies, posterior embryotoxon in the eye (Digital Reference of Ophthalmology: Cornea & External Diseases [Accessed 25 October 2017]), pulmonary stenosis or more severe congenital heart disease, butterfly vertebrae or other vertebral arch anomalies, other skeletal anomalies such as short distal phalanges or clinodactyly
    • Several renal abnormalities such as tubulointerstitial nephropathy, membranous nephropathy, mesangiolipidosis, renovascular hypertension, etc. have been reported
  • Liver findings are characterized by progressive loss of bile ducts with or without hypoplasia of extrahepatic bile ducts (Nat Genet 1997;16:235), hypoplasia of gallbladder and cholelithiasis (Nat Genet 1997;16:235) leading to jaundice and pruritus
    • It can mimic other causes of high GGT cholestasis, particularly biliary atresia
Microscopic (histologic) description
  • Portal tracts are devoid of bile ducts; the ratio of bile ducts to portal tracts is 0 to 0.4 (normal 0.9 to 1.8) (Pediatr Pathol 1988;8:1)
  • Ductular reaction is typically absent but rare examples present with ductular reaction in early infancy (Nat Genet 1997;16:235)
  • Giant cell transformation and periportal copper deposits can be seen
  • Progression to cirrhosis is rare
  • Liver transplantation is reserved for patients with progressive liver disease or intractable pruritus
  • Mortality is related to liver disease, cardiac abnormalities and intracranial bleeding
  • Patients may survive into adulthood but with increased risk of hepatic failure and hepatocellular carcinoma
  • Microscopic (histologic) images

    Contributed by Kalyani R. Patel, M.D.
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    Liver biopsies

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