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Background & Aims: 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 E 2 (PGE 2 ) and other lipids., Methods: We analyzed bloods samples from 45 of 79 patients with AD/ACLF and serum levels of albumin less than 30 g/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 PGE 2 and serum levels of endotoxin (lipopolysaccharide) and cytokines; using 10 patients' samples, we investigated the effects of PGE 2 inhibitors. We performed a comprehensive lipid metabolomic analysis using samples from 10 different patients, before and after HAS administration., Results: At baseline, AD/ACLF patient plasma induced significantly lower production of tumor necrosis factor by healthy macrophages than plasma from healthy individuals (P < .0001). Plasma from patients after HAS infusion induced significantly higher levels of tumor necrosis factor 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 PGE 2 from patients with AD/ACLF plasma (mean, 61.9%) compared with plasma from control subjects (77.1%; P = .0012). AD/ACLF plasma protein binding to PGE 2 increased following HAS treatment compared with baseline (mean increase, 8.7%; P < .0001). Circulating levels of PGE 2 , lipopolysaccharide, 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 lipopolysaccharide. Sample analyses after HAS treatment indicated that albumin regulates circulating levels of lipid mediators, but this effect was distinct in each group., Conclusions: Analysis of blood samples from patients with AD/ACLF participating in a feasibility study of 20% HAS infusions has shown that infusions to raise serum albumin above 30 g/L reversed plasma-mediated immune dysfunction by binding and inactivating PGE 2 . We also describe a method to classify the inflammatory response in AD/ACLF, based on lipid profile, which 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. Trial registered with European Medicines Agency (EudraCT 2014-002300-24) and adopted by NIHR (ISRCTN14174793)., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Infections are life-threatening to patients with acute decompensation and acute-on-chronic liver failure (AD/ACLF). Patients with AD/ACLF have prostaglandin E2-mediated immune suppression, which can be reversed by administration of albumin; infusion of 20% human albumin solution (HAS) might improve outcomes of infections. We performed a feasibility study to determine optimal trial design, assess safety, and validate laboratory assessments of immune function to inform design of a phase 3 trial., Methods: We performed a prospective multicenter, single-arm, open-label trial of 79 patients with AD/ACLF and levels of albumin lower than 30 g/L, seen at 10 hospitals in the United Kingdom from May through December 2015. Patients were given daily infusions of 20% HAS, based on serum levels, for 14 days or until discharge from the hospital. Rates of infection, organ dysfunction, and in-hospital mortality were recorded. The primary end point was daily serum albumin level during the treatment period. Success would be demonstrated if 60% achieved and maintained serum albumin levels at or above 30 g/L on at least one third of days with recorded levels., Results: The patients' mean model for end-stage disease score was 20.9 ± 6.6. The primary end point (albumin ≥30 g/L on at least one third of days recorded) was achieved by 68 of the 79 patients; 75% of administrations were in accordance with suggested dosing regimen. Mean treatment duration was 10.3 days (104 ± 678 mL administered). There were 8 deaths and 13 serious adverse events, considered by the independent data-monitoring committee to be consistent with those expected. Twelve of 13 patients that developed either respiratory or cardiovascular dysfunction (based on ward-based clinical definitions) as their only organ dysfunction were alive at 30 days compared with 1 of 3 that developed renal dysfunction. Only 1 case of brain dysfunction was recorded., Conclusions: In a feasibility trial, we found that administration of HAS increased serum levels of albumin in patients with AD/ACLF. The dosing regimen was acceptable at multiple sites and deemed safe by an independent data-monitoring committee. We also developed a robust system to record infections. The poor prognosis for patients with renal dysfunction was confirmed. However, patients with cardiovascular or respiratory dysfunction had good outcomes, which is counterintuitive. Severe encephalopathy appeared substantially under-reported, indicating that ward-based assessment of these parameters cannot be recorded with sufficient accuracy for use as a primary outcome in phase 3 trials. Trial registration no: EudraCT 2014-002300-24 and ISRCTN14174793., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)