We have studied 92 patients with Alagille syndrome (AGS) to determine the frequency of clinical manifestations and to correlate the clinical findings with outcome. Liver biopsy specimens showed paucity of the interlobular ducts in 85% of patients. Cholestasis was seen in 96%, cardiac murmur in 97%, butterfly vertebrae in 51%, posterior embryotoxon in 78%, and characteristic facies in 96% of patients. Renal disease was present in 40% and intracranial bleeding or stroke occurred in 14% of patients. The presence of intracardiac congenital heart disease was the only clinical feature statistically associated with increased mortality (P F .001). Initial measures of hepatic function in infancy including absence of scintiscan excretion were not predictive of risk for transplantation or increased mortality. The hepatic histology of these AGS patients showed a significant increase in the prevalence of bile duct paucity (P β«Ψβ¬ .002) and fibrosis (P F .001) with increasing age. Liver transplantation for hepatic decompensation was necessary in 21% (19 of 92) of patients with 79% survival 1-year posttransplantation. Current mortality is 17% (16 of 92). The factors that contributed significantly to mortality were complex congenital heart disease (15%), intracranial bleeding (25%), and hepatic disease or hepatic transplantation (25%). The 20-year predicted life expectancy is 75% for all patients, 80% for those not requiring liver transplantation, and 60% for those who required liver transplantation. (HEPATOLOGY 1999;29:822-829.)
Alagille syndrome (AGS) is an autosomal dominant disorder that involves abnormalities of varying severity in multiple organ systems. [1][2][3][4][5][6] The diagnosis of AGS traditionally has been based on the finding of paucity of the interlobular bile ducts associated with three to five major features: chronic cholestasis, cardiac disease, skeletal abnormalities, ocular abnormalities, and a characteristic facial phenotype. The phenotypic findings in AGS are highly variable in severity and clinical significance. In a single family, one patient may present with life-threatening congenital heart disease, whereas others may possess only subtle manifestations. 7 The wide range of affected organs coupled with the variable severity of involvement at each site makes overall clinical prognostication difficult. The phenotypic spectrum of clinical AGS has recently been shown to be because of defects in a single gene, Jagged1, which encodes a ligand in the developmentally important Notch intercellular signaling pathway. 8,9 The mechanism by which defects in Jagged1 cause AGS is not currently understood. Preliminary studies have not shown a relationship between genotypes and specific disease phenotypes in AGS. 10 The goals of this retrospective study of 92 individuals with AGS are: (1) to report the prevalence of the major and minor clinical features of AGS, (2) to describe the findings and discuss the implications of diagnostic testing in infants at initial presentation, (3) to review the initial and subsequent hepatic histology, and (4) to determine if clinical features predict morbidity, transplantation, or death.