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A new study from the GALA cohort shows serum bile acid's association with clinical outcomes is relevant in the context of IBAT inhibitor therapy.
Serum bile acid is an independent predictive risk factor for native liver survival among pediatric patients with Alagille syndrome and neonatal cholestasis, according to a new analysis.
In new research from the Global Alagille Alliance (GALA) Study Group’s global patient cohort, investigators observed a positive correlation between serum bile acid and total bilirubin in patients, as well as a clinically-relevant association between such levels in the context of ileal bile acid transporter (IBAT) inhibitors that which have been noted to reduce bile acid levels in patients with cholestatic diseases including Alagille syndrome.
The data were presented by study author C. Fiorella Murillo Perez, PhD, MS, associate director of medical affairs evidence generation and real-world evidence with CymaBay Therapeutics, at The Liver Meeting 2023 from the American Association for the Study of Liver Diseases (AASLD) in Boston this weekend.
Though investigators previously established bilirubin as a predictor of clinical outcomes including risk of liver transplantation or death in patients with Alagille syndrome, Perez and colleagues sought to determine whether serum bile acid levels are predictive of liver disease outcomes in such patients—as well as the prognostic value of bile acids in the context of bilirubin.
“IBAT inhibitors reduce serum bile acids in cholestasis, yet implications for outcomes remain to be elucidated,” Perez and colleagues wrote. Previously, patients treated with maralixibat in the GALA cohort showed a 70% reduced risk for clinical events including biliary diversion surgery, decompensation event, liver transplantation, or death compared to natural history.
The investigators used patients from the >1600-individual cohort across 74 sites in 32 countries for their analysis. Eligible patients were diagnosed with clinically or genetically confirmed Alagille syndrome between January 1997 – August 2019, or just genetically confirmed disease prior to January 1997. Patients were additionally required to have neonatal cholestasis and ≥1 serum bile acid value.
Among the 1525 patients eligible for the GALA cohort, 1259 had neonatal cholestasis. Of them, 570 patients had ≥1 serum bile acid measurement and adequate clinical information during eligibility follow-up and were included in the assessment. Across the patient population, investigators reported 2629 serum bile acid values.
Of the values, 57% (n = 1497) were measured within the first 2 years of the patient’s life. The median (50th percentile) of serum bile acid score was 140.1 umol/L.
Regarding clinical events, investigators observed 96 transplants and 25 deaths among the cohort. There were additionally 161 cases of portal hypertension, biliary diversion, liver transplant or death.
Perez and colleagues observed a moderate positive correlation between patient serum bile acid and bilirubin (Pearson correlation, 0.47; P <.001). They additionally found a significant time-dependent association between serum bile acid levels >102 umol/L and clinical outcomes including native liver survival (hazard ratio [HR], 3.78; 95% CI, 2.39 – 5.99; P <.001) and event-free survival (HR, 3.44; 95% CI, 2.35 – 5.04; P <.001).
Even when adjusting for bilirubin, the team observed a significant time-dependent association between such serum bile acid levels and those clinical outcomes at 1 year. What’s more, a median serum bile acid level in the first year was associated with native liver survival (P = .05).
The team concluded their findings showed a positive correlation between total bilirubin and serum bile acid; a trend of continued elevated bile acid in patients who met a clinical endpoint, versus a decrease in bilirubin over time and greater decrease in those without a clinical endpoint; a serum bile acid threshold of 102 umol/L as a significant time-dependent and bilirubin-independent predictor of clinical outcomes; and an associated between median first-year serum bile acid levels and clinical outcomes.
“Serum bile acid is an independent predictive factor for native liver survival in patients with Alagille syndrome and neonatal cholestasis,” Perez said. “Its association with clinical outcomes is relevant in the context of IBAT inhibitors that are now able to reduce serum bile acids, and there’s a potential for serum bile acid levels to be used as a prognostic factor in patients already low bilirubin levels.
Vandriel SM, Wang JS, Li LT, She H, et al. SERUM BILE ACIDS ARE ASSOCIATED WITH NATIVE LIVER SURVIVAL IN PATIENTS WITH ALAGILLE SYNDROME: RESULTS FROM THE GALA STUDY GROUP. Paper presented at: The Liver Meeting. Boston, MA. November 10 - 14, 2023.