Alagille syndrome (ALGS) affects multiple organ systems and is characterized by clinical manifestations such as bile duct paucity, cholestasis, congenital cardiac defects, eye abnormalities, distinct facial features, and skeletal malformations. Other abnormalities may include growth failure, renal abnormalities, developmental delays, splenomegaly, and vascular abnormalities.
Alagille syndrome is suspected in patients if the histological findings, mainly from the liver, show bile duct paucity and other features discussed below. These findings are only suggestive of ALGS. Diagnosis is established using the gold-standard method of genetic testing to identify disease-causing gene mutations, most often in the JAG1 or NOTCH2 gene.1
Bile Duct Paucity
The most important and consistent feature, as revealed by the histological examination of liver biopsy specimens from patients with ALGS, is the reduction in the number of bile ducts within the portal tracts, a condition termed intrahepatic bile duct paucity.1 This feature is observed in about 90% of ALGS cases. Bile duct paucity seems to progress with time, as it is observed in only 60% of infants below 6 months of age, while it is more common (95%) in infants above 6 months of age, and adults. Thus, the ratio of bile ducts to portal tracts in ALGS patients is very low — around 0 to 0.4, in contrast to the normal ratio of 0.9 to 1.8.2
However, in rare cases of infants aged less than 6 months, the liver biopsy may demonstrate bile duct proliferation (usually with portal inflammation) instead of bile duct paucity, making it difficult to diagnose ALGS and misdiagnosing it as biliary atresia. As the infant grows, the bile ducts gradually reduce in number, a characteristic feature of ALGS.3
Progressive end-stage liver disease requiring liver transplantation occurs in only about 15% of ALGS cases. Although no histologic finding can predict the severity of liver disease in ALGS, a study by Mouzaki et al. showed that poor hepatic outcomes in ALGS patients can be predicted by high levels of serum bilirubin within the first 1 to 2 years of life, as well as by hepatic fibrosis as revealed by liver biopsy and presence of xanthomas.4
The mortality rate for ALGS is approximately 20% to 25% and is mainly associated with cardiac disease, progressive liver disease, or intracranial bleeding.5 If patients survive, they are at a higher risk of developing hepatocellular carcinoma.
Ductular reaction is generally not found in patients with ALGS. However, in rare cases of infants aged less than 6 months, histologic examination of liver samples may reveal minimal ductular reaction around the portal tracts.6,7
Other features that may be observed in the biopsy specimens are normal parenchyma structure, reduced number of portal tracts, giant cell transformation (enlarged hepatocytes with several nuclei), significant intracellular and canalicular cholestasis, deposition of copper in periportal hepatocytes, and mild to moderate inflammation in the portal areas.3,7
Histology for Diagnosis of ALGS
The revised diagnostic criteria specify that the diagnosis of ALGS can be made by histological examination of liver specimens, along with the presentation of at least 3 of the 5 clinical features — heart murmur, eye abnormalities (posterior embryotoxon), butterfly-like vertebrae, renal abnormalities, and characteristic facial features. However, histological examination is not required for diagnosis. If the liver biopsy is not performed, diagnosis can be made by the presence of at least 4 of the 5 features.3
Histology for Differential Diagnosis of ALGS
In adults and children aged more than 6 months, histological examination of liver biopsy specimens can help differentiate ALGS from biliary atresia. This is because liver samples from ALGS patients reveal a decrease in the number of interlobular bile ducts located close to the central vein, while samples from patients with biliary atresia show bile duct proliferation near the periphery.8 In addition, patients with ALGS have no ductular reaction or hepatic progenitor cells, progression to cirrhosis is slower, and they rarely develop portal hypertension, compared to patients with biliary atresia who have severe cholestasis leading to pronounced ductular reaction with increased number of hepatic progenitor cells and rapid progression to liver cirrhosis.9
- Spinner N, Gilbert M, Loomes K, Krantz ID. Alagille syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews®. University of Washington, Seattle; 1993-2021. Updated December 12, 2019. Accessed May 27, 2021.
- Hashida Y, Yunis EJ. Syndromatic paucity of interlobular bile ducts: hepatic histopathology of the early and endstage liver. Fetal Pediatr Pathol. 1988;8(1):1-15. doi:10.3109/15513818809022275
- Wang JS, Wang XH, Zhu QR, Wang ZL, Hu XQ, Zheng S. Clinical and pathological characteristics of Alagille syndrome in Chinese children. World J Pediatr. 2008;4(4):283-288. doi:10.1007/s12519-008-0051-5
- Saleh M, Kamath BM, Chitayat D. Alagille syndrome: clinical perspectives. Appl Clin Genet. 2016;9:75-82. doi:10.2147/TACG.S86420
- Arroyo M, Crawford JM. Pediatric liver disease and inherited, metabolic, and developmental disorders of the pediatric and adult liver. In: Odze R, Goldblum J, eds. Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas. 2nd ed. Elsevier Inc.; 2009:1245-1290. Accessed June 24, 2021.
- Gilbert MA, Loomes KM. Alagille syndrome and non-syndromic paucity of the intrahepatic bile ducts. Transl Gastroenterol Hepatol. 2021;6:22. doi:10.21037/tgh-2020-03
- Alagille syndrome. Pathology outlines. Accessed May 27, 2021.
- Singh SP, Pati GK. Alagille syndrome and the liver: current insights. Euroasian J Hepato-Gastroenterology. 2018;8(2):140-147. doi:10.5005/jp-journals-10018-1280
- Fabris L, Cadamuro M, Guido M, et al. Analysis of liver repair mechanisms in Alagille syndrome and biliary atresia reveals a role for Notch signaling. Am J Pathol. 2007;171(2):641-653. doi:10.2353/ajpath.2007.070073
Reviewed by Debjyoti Talukdar, MD, on 7/1/2021.