Blood bile acids predict liver outcomes in Alagille syndrome children: Study
New biomarker could be targeted as a therapeutic strategy
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Children with Alagille syndrome who have lower blood levels of bile acids, the main component of the digestive fluid bile, have better long-term liver health and fewer serious complications, according to a real-world study involving nearly 600 children worldwide.
Bile acid levels even predicted liver outcomes among Alagille children who cleared bilirubin, a blood marker of liver damage, within the first year of life, the data showed.
According to researchers, the findings suggest that approved therapies designed to lower blood bile acid levels to prevent itching, a common Alagille symptom, may also preserve liver function.
“The current analysis sheds light on the role of [blood bile acids] in the [underlying mechanisms] of liver disease progression in ALGS [Alagille syndrome] and provides a rationale for targeting bile acids as a therapeutic strategy,” researchers wrote.
The study, “Elevated Serum Bile Acids Predict Poor Liver Outcomes in Children With Alagille Syndrome: Results From the GALA Study Group,” was published in Liver International.
Researchers examined real-world data on children
Alagille syndrome is a genetic disorder present from birth that’s characterized by a reduced number of bile ducts, the tubes that carry bile from the liver to the intestines. With fewer ducts, bile can’t drain properly and builds up to toxic levels in the liver, damaging the organ and leaking into the bloodstream. This can cause symptoms such as itching (pruritus) and ultimately lead to liver failure, where a liver transplant is the only therapeutic option.
Measuring the blood levels of total bilirubin is an established method to predict outcomes in people with liver disease, with high sustained levels being associated with an increased risk of liver transplant or death.
While itching is known to be driven by elevated blood bile acid levels, it remains unclear whether these levels can predict liver-related outcomes in children with Alagille.
To address this gap, an international team of researchers examined real-world data from children with Alagille participating in the Global Alagille Alliance (GALA) study, the largest natural history study in Alagille.
“We hypothesized that [blood bile acid] levels can independently and in conjunction with [total bilirubin] predict long-term [liver] outcomes,” the researchers wrote.
Blood bile acid levels a significant predictor of event-free survival
The study included 570 pediatric Alagille patients (61% boys) from several regions, such as Asia (38.2%), Europe (35.3%), North America (19.5%), Australia and New Zealand (4.2%), the Middle East (2.6%), and Africa (0.2%).
Most children (63%) had available data on blood bile acid levels from at least two measurements, with more than a third (37%) having at least five measurements. The median bile acid level in the first two years of life was 147 micromoles per liter (mcmol/L), markedly above the normal range of 10 mcmol/L or less.
The native liver survival (NLS) rates, or the proportion of live children who did not need a liver transplant, were 81.1% at five years, 59.3% at 10 years, and 53.6% at 18 years.
The event-free survival (EFS) rates, or the proportion of children who lived without a liver disease-related event were 75% at five years, 58.7% at 10 years, and 46.1% at 18 years. Events included surgery to reroute bile flow, manifestations of severe liver disease, liver transplant, or death.
Statistical analyses showed that blood bile acid levels were significantly associated with higher blood bilirubin levels.
Bile acid levels remained high over time in patients who later required a liver transplant or died, but did not rise immediately beforehand. In contrast, total bilirubin fell after birth — more so in children with better outcomes — and rose sharply before liver transplant or death.
The data presented here reveal that [blood bile acid] is a biomarker of liver disease severity in ALGS and lower [blood bile acid] levels are associated with improved markers of liver disease severity (platelet count) and [liver transplant/death].
Further analysis demonstrated that a threshold of 102 mcmol/L in bile acid levels best predicted NLS rates. In about one-fourth (27%) of the children in the study, levels were maintained below this threshold during follow-up. The median time children took from birth to reach such a threshold was 0.84 years (about 10 months).
Children with bile acid levels lower than 102 mcmol/L had a more than 3.5 times higher chance of NLS (liver transplant or death) and a threefold higher chance of EFS. Below-threshold values were also significantly associated with a more than 2.5 times higher chance of a drop in platelet counts, a marker of severe liver disease. Platelets are cell fragments that help blood clot.
Blood bile acid levels remained a significant predictor of EFS after adjusting for total bilirubin clearance at 1 year of age.
“Even in patients with ALGS who clear their [bilirubin] by the age of 1 year, [blood] bile acid remains a significant predictor of liver disease outcome,” the team wrote.
Also, a median bile acid level above 102 mcmol/L in the first year was associated with lower rates of NLS (67.2% vs. 83.5%), EFS (63.4% vs. 80.9%), EFS with low platelet counts (58.5% vs. 73.7%), and low platelet counts alone (19.3% vs. 10.1%) at 7 years of age. The results remained consistent when the bile acid level threshold was set at 200 mcmol/L.
“The data presented here reveal that [blood bile acid] is a biomarker of liver disease severity in ALGS and lower [blood bile acid] levels are associated with improved markers of liver disease severity (platelet count) and [liver transplant/death],” the researchers wrote. “These data provide a practical tool for clinicians caring for patients with ALGS, especially those who clear their [high bilirubin levels].”
