Early life predictive markers of liver disease outcome in an International, Multicentre Cohort of children with Alagille syndrome

Abstract

Background and Aims Liver disease in Alagille syndrome is highly variable. Many of these patients presenting with severe cholestasis early in life improve spontaneously; 10–20% however, have progressive disease. It is currently not possible to predict long-term hepatic outcomes in Alagille syndrome. This international, multicenter study was aimed at identifying early life predictors of liver disease outcome. Methods Retrospective clinical, laboratory and radiographic data from a cohort of 144 Alagille syndrome patients, whose long-term hepatic outcomes had been determined a priori based on previously published criteria, were collected. Results Sixty-seven had mild and 77 severe hepatic outcome. Univariate analysis demonstrated that cholestasis and fibrosis on biopsy, as well as the presence of xanthomata were significantly different between the groups (p<0.05 for all). Mixed model analysis revealed that total serum bilirubin and serum cholesterol were also associated with outcome (p=0.001 and p=0.002, respectively). Graphical representation of the data revealed a change in total bilirubin levels between 12 and 24 months of age in the mild group. Recursive partitioning identified a threshold for total bilirubin of 3.8 mg/dL (65mmol/L) in that age-frame that differentiated between outcomes. A multivariable logistic regression model was developed using fibrosis, xanthomata and the total bilirubin cutoff of 3.8 mg/dL (65mmol/L), which generated an area under the ROC of 0.792. Conclusions The long-term hepatic outcomes of patients with Alagille syndrome can be predicted based on serum total bilirubin between the ages of 12–24 months combined with fibrosis on liver biopsy and presence of xanthomata on physical examination.

Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome

“…To examine whether SOX9 expression level and pattern in the liver correlates with liver disease severity and outcome in ALGS patients, we obtained liver samples (biopsy or explant) from 10 patients with ALGS from Texas Children’s Hospital whom we could categorize as mild (n = 3) or severe (n = 7) (Fig. A) based on serum bilirubin levels, liver fibrosis in pathology reports, the follow‐up information in patient files, and their transplant status . Of note, quantification of the BD to PV ratio showed a correlation between the BD density and liver disease severity in mild versus severe patients (Supporting Fig.…”

“…With an estimated frequency of 1:30,000, ALGS is the most common genetic disease resulting in intrahepatic cholestasis. (11) The course of the liver disease is quite variable in patients with ALGS. First, phenotypes span from mild biochemical abnormalities to profound cholestasis.…”

“…(4,12) A strong correlation has been established between a number of early life markers and the outcome of liver disease in patients with ALGS. (11) However, there is no genotype-phenotype correlation in ALGS, (11,(13)(14)(15) and the basis for variability in disease presentation and outcome is not known. Moreover, a mechanism-based therapy does not exist for the ALGS liver phenotypes.…”

“…Second, approximately half of the patients who present with severe cholestasis at a young age show improvement or stop progression of their liver disease, while others require a liver transplant . A strong correlation has been established between a number of early life markers and the outcome of liver disease in patients with ALGS . However, there is no genotype–phenotype correlation in ALGS, and the basis for variability in disease presentation and outcome is not known.…”

Alagille Syndrome: Genetics and Functional Models

“…Multiple studies have sought to identify predictive factors that will allow clinicians to distinguish who will likely advance to end-stage liver disease and require a transplant, but these studies have met with varying success [31–33]. Although it was found that liver disease status under 5 years of age was not a stable predictor of long-term disease progression, a new prognostic method, which analyzes serum total bilirubin, liver biopsy fibrosis, and xanthomas, has shown some benefit in helping to predict the likelihood for future liver transplant [31, 32]. …”