Cytokine levels may predict Kasai procedure outcome in biliary atresia
Study finds levels of immune molecules may be linked to surgery's success
Blood levels of certain immune signaling molecules called cytokines may help to predict the likelihood of a successful outcome with the Kasai procedure — a surgery used as a first-line treatment — in children with biliary atresia, a study from scientists across the U.S. and Canada reports.
“If confirmed across larger patient [groups], these findings hold the potential to develop new prognostic biomarker panels to help stratify patients for interventional trials and to eventually guide patient-specific treatment plans,” the researchers wrote.
According to the team, these results “address a gap in the understanding of how different … immune [profiles] relate to patient outcomes.” As such, the findings “[provide] novel insight into early disease [mechanisms] that may impact patient outcomes,” they wrote.
The study, “Increased serum GM-CSF at diagnosis of biliary atresia is associated with improved biliary drainage,” was published in the journal Pediatric Research.
Investigating the factors underlying a successful Kasai procedure outcome
Biliary atresia is a congenital disorder in which the bile ducts are blocked or missing. Bile ducts are a series of tubes that carry the digestive fluid bile out of the liver to the intestines; in biliary atresia, bile cannot flow properly, so it builds up and damages the liver.
The Kasai procedure, more formally known as Kasai portoenterostomy, is a surgery that aims to create new channels for bile to flow from the liver to the intestines. When successful, the surgery can help normalize bile flow and reduce liver damage.
However, the Kasai procedure doesn’t always result in a successful outcome in restoring bile flow, for reasons that aren’t fully understood. To date, scientists have identified several factors that have been associated with poor outcomes after Kasai surgery. These include older age at the time of the procedure.
Other factors linked to poor outcomes are higher levels of the MMP-7 molecule and high levels of IL-8, a pro-inflammatory molecule. The infiltration of macrophages, a type of immune cell, in vessels that supply the liver also has been cited as a factor.
Now, a team of researchers examined whether the activity of macrophages in the liver may affect the likelihood of success following the Kasai surgery. The researchers specifically looked at levels of several cytokines, or immune signaling molecules, that help to coordinate the activity of macrophages and other immune cells.
“As macrophages can serve both pro- or anti-inflammatory roles in [biliary atresia] and these roles can be influenced by the tissue microenvironment, discerning how specific macrophage networks influence patient outcome could help develop improved prognostic biomarkers and identify novel therapeutic targets,” the team wrote.
Liver tissue and blood samples were analyzed from 38 infants with biliary atresia who subsequently underwent the Kasai procedure. The procedure effectively reestablished bile flow in 20 of the patients, but not in the other 18.
In terms of types of macrophages in the liver before surgery, infants with successful biliary drainage after the Kasai procedure showed more monocyte-like macrophages, called MLMs.
While no significant differences in the number of lipid-associated macrophages, or LAMs, were found between the two groups of patients, having more LAMs was significantly associated with worse biliary drainage and higher levels of liver damage markers.
In addition, blood levels of a cytokine called granulocyte-macrophage colony stimulating factor (GM-CSF) were significantly higher in infants who had a successful outcome from the Kasai procedure. Higher GM-CSF levels were significantly associated with levels of three cytokines: IL-16, c-reactive protein, and TNF-beta.
Researchers seeking prognostic markers for surgery in children
To assess the utility of these cytokines as prognostic markers, the researchers used a statistical test called the area under the receiver operating characteristic curve, or AUC.
This metric evaluates how well a test can distinguish between two groups — in this case, infants with versus without successful post-Kasai bile flow restoration. AUC values range from 0 to 1, with 0.5 indicating random guessing and 1 reflecting perfect predictive performance.
We identified an immune signature among [biliary atresia] participants at diagnosis that is associated with successful biliary drainage after [the Kasai procedure].
When the researchers used only blood GM-CSF levels at diagnosis, the test’s AUC value was 0.75, suggesting somewhat good predictive performance.
When levels of GM-CSF were analyzed alongside those of IL-16, c-reactive protein, and TNF-beta, the test’s ability to discriminate between infants with a successful Kasai procedure outcome and those without markedly improved. Specifically, it showed an AUC of 0.84, the researchers noted.
“We identified an immune signature among [biliary atresia] participants at diagnosis that is associated with successful biliary drainage after [Kasai portoenterostomy], including higher [liver] MLM and lower LAM numbers and increased [blood] GM-CSF levels,” the team wrote.
According to the researchers, “our study suggests that [GM-CSF-activated MLMs] at the time of diagnosis may promote an anti-inflammatory immune response that improves future biliary drainage” after the Kasai procedure, the researchers wrote.
The team stressed that further research is needed to expand on these findings.
“Confirmation of the prognostic accuracy of this immune [profile] in independent [biliary atresia patient groups] is needed along with mechanistic studies to more precisely define the impact of macrophage polarization on disease progression,” the researchers wrote.
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