Patients with acute decompensation and acute on chronic liver failure (AD/ACLF) have immune dysfunction, which increases their risk for infections; however there are no effective treatments to restore their immune function. We investigated whether the potentially immune-restorative effects of albumin are mediated by its effects on prostaglandin E2 (PGE2) and other lipids.
We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30g/L for whom infusion of 20% human albumin solution (HAS) increased serum levels of albumin 30 g/L or more in a feasibility study of effects of 20% HAS. Immune function was determined by comparison of macrophage function following addition of plasma samples. We also used samples from 12 healthy individuals. We measured binding of plasma proteins to PGE2 and serum levels of endotoxin (LPS) and cytokines; using 10 patients' samples, we investigated the effects of PGE2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration.
At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor (TNF) by healthy macrophages than plasma from healthy individuals (P<.0001). Plasma from patients after HAS infusion induced significantly higher levels of TNF production by macrophages (19.5±4.8 ng/ml) compared with plasma collected before treatment (17.7±4.5 ng/ml) (P=.0013). There was a significantly lower proportion of plasma protein (albumin) binding to PGE2 from AD/ACLF patients plasma (mean 61.9%) compared to plasma from controls (77.1%) (P=.0012). AD/ACLF plasma protein binding to PGE2 increased following HAS treatment compared with baseline (mean increase 8.7%,P<.0001). Circulating levels of PGE2, LPS, and inflammatory or anti-inflammatory cytokines were higher in patients with AD/ACLF than healthy volunteers. Unexpectedly, HAS infusion had no effect on mediator levels. Principal component analysis of baseline levels of lipids that induce or resolve inflammation identified 2 distinct groups of patients that differed according to baseline plasma level of LPS. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group.
Analysis of blood samples from AD/ACLF patients participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE2. We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, that could improve identification of patients most likely to respond to HAS treatment. A randomized controlled trial is needed to determine whether these effects of HAS reduce infections in AD/ACLF.
This research output has an Altmetric Attention Score of 24. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 15 September 2023.
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