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Background and aims--Various opinions have been expressed as to the long term prognosis of liver disease associated with Alagille syndrome (AGS).
Patients and methods--We reviewed the outcome of 163 children with AGS and liver involvement, investigated from 1960 to 2000, the end point of the study (median age 10 years (range 2 months to 44 years)) being death, liver transplantation, or the last visit.
Results--At the study end point, of the 132 patients who presented with neonatal cholestatic jaundice, 102 remained jaundiced, 112 had poorly controlled pruritus, and 40 had xanthomas; cirrhosis was found in 35/76 livers, varices in 25/71 patients, and liver transplantation had been carried out in 44 patients (33%). Forty eight patients died, 17 related to complications of liver disease. Of 31 patients who did not present with neonatal cholestatic jaundice, five were jaundiced at the study end point, 17 had well controlled pruritus, and none had xanthomas; cirrhosis was found in 6/18 patients, varices in 4/11, and none underwent liver transplantation. Nine patients died, two of liver disease. In the whole series, actuarial survival rates with native liver were 51% and 38% at 10 and 20 years, respectively, and overall survival rates were 68% and 62%, respectively. Neonatal cholestatic jaundice was associated with poorer survival with native liver (p=0.0004).
Conclusions--The prognosis of liver disease in AGS is worse in children who present with neonatal cholestatic jaundice. However, severe liver complications are possible even after late onset of liver disease, demanding follow up throughout life.
Keywords: Alagille syndrome; cholestasis; end stage liver disease; liver transplantation
Syndromic paucity of interlobular bile ducts (Alagille syndrome, AGS) is an autosomal dominant disorder defined clinically by the association of at least three of five major features (chronic cholestasis, congenital heart disease, "butterfly-like" vertebrae, posterior embryotoxon, and peculiar facies) and genetically by mutations in the Jagged 1 gene. [1-3] Expression of AGS varies from a mild phenotype to severe diseases of the heart or kidney and to the consequences of chronic cholestasis, including liver failure. AGS has long been said to have a relatively good long term prognosis in terms of liver disease [4 5]; however, it is now well recognised that some patients with AGS can present with severe complications of liver disease. [6-12] We therefore reviewed the charts of 174 patients with AGS presenting in childhood to evaluate the role of the liver condition in mortality, morbidity, and long term outcome.
Patients and methods
One hundred and seventy four children with AGS (106 boys) were investigated at Bicetre Hospital between 1960 and 2000. Twenty four had a sibling affected by AGS; seven of these siblings are included in this series as well as two offspring of affected mothers. All patients had at least three of the five major clinical features. Thirteen children with severe neonatal jaundice underwent K.asai operation for suspected biliary atresia before the diagnosis of AGS was established. Cholecystostomies with external bile drainage and cholecystojejunal anastomoses were performed in 24 and six patients, respectively. End stage liver disease was defined by the combination of the following laboratory tests: serum bilirubin concentration [greater than]300 limol/l, serum albumin concentration [less than]35 g/l, and prolonged prothrombin time in spite of treatment with parenteral vitamin K. Investigations of portal hypertension included upper digestive endoscopy, ultrasonography, and angiography. Therapy included various antip ruritus drugs over time and supplementation as necessary with parenteral or oral fat soluble vitamins. Hypercaloric continuous nocturnal enteral feeding was performed in 39 children with severe growth and height retardation.
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