Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure

Background and AimsAcute-on-chronic liver failure (ACLF) is characterized by systemic inflammation accompanied by defective anti-bacterial immunity. The role of neutrophils in immune derangement of ACLF has not been fully elucidated. This study is aimed to characterize the role of circulating neutrophils in HBV-related ACLF patients.MethodsQuantitative, phenotypic, transcriptomic, and functional alterations of circulating neutrophils were compared in ACLF and non-ACLF subjects and analyzed for associations with short-term outcomes. Interventional experiments were performed to test the impact on ACLF-patient neutrophil function in vitro.ResultsCirculating absolute neutrophil count was significantly increased in patients with ACLF and was an independent risk factor for 28-day mortality. ACLF-patient neutrophils differentially expressed a panel of surface markers (include TLR-1, TLR-2, TLR-4, CEACAM-1 and FPR1), as well as a distinct transcriptomic signature. ACLF-neutrophils displayed significantly impaired phagocytosis but an increased capacity to form neutrophil extracellular traps (NETs), which was more pronounced in patients with poor outcome. Healthy neutrophils mimicked functional characteristics of ACLF counterpart after co-cultured with plasma from ACLF patients. The oxidative burst and cytokine production capacities remained unchanged. Plasma GM-CSF, IL-6, IL-8, IL-10, and IP-10 levels, as well as lipopolysaccharide (LPS) concentration, were markedly elevated in ACLF patients but not DAMP molecules HMGB-1 and HSP70. Finally, a glycolysis inhibitor, 2-deoxy-glucose, reduced NET formation of ACLF patients’ neutrophils.ConclusionsCirculating ACLF-patient neutrophils exhibit alterations in number, phenotype, gene expression and function, which was associated with poor outcome and shaped by the ACLF circulatory environment. Inhibiting glycolysis can reverse neutrophil dysfunction in ACLF patients.

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Inhibition of glutamine synthetase in monocytes from patients with acute-on-chronic liver failure resuscitates their antibacterial and inflammatory capacity

Gut ◽

10.1136/gutjnl-2018-316888 ◽

2018 ◽

Vol 68 (10) ◽

pp. 1872-1883 ◽

Cited By ~ 16

Author(s):

Hannelie Korf ◽

Johannie du Plessis ◽

Jos van Pelt ◽

Sofie De Groote ◽

David Cassiman ◽

...

Keyword(s):

Glutamine Synthetase ◽

Liver Failure ◽

Bacterial Infections ◽

Chronic Liver ◽

Decompensated Cirrhosis ◽

Chronic Liver Failure ◽

Phenotypic Characterisation ◽

Severity Scores ◽

Aclf Patient

ObjectiveAcute-on-chronic liver failure (ACLF) is associated with dysfunctional circulating monocytes whereby patients become highly susceptible to bacterial infections. Here, we identify the pathways underlying monocyte dysfunction in ACLF and we investigate whether metabolic rewiring reinstates their phagocytic and inflammatory capacity.DesignFollowing phenotypic characterisation, we performed RNA sequencing on CD14+CD16− monocytes from patients with ACLF and decompensated alcoholic cirrhosis. Additionally, an in vitro model mimicking ACLF patient-derived features was implemented to investigate the efficacy of metabolic regulators on monocyte function.ResultsMonocytes from patients with ACLF featured elevated frequencies of interleukin (IL)-10-producing cells, reduced human leucocyte antigen DR isotype (HLA-DR) expression and impaired phagocytic and oxidative burst capacity. Transcriptional profiling of isolated CD14+CD16− monocytes in ACLF revealed upregulation of an array of immunosuppressive parameters and compromised antibacterial and antigen presentation machinery. In contrast, monocytes in decompensated cirrhosis showed intact capacity to respond to inflammatory triggers. Culturing healthy monocytes in ACLF plasma mimicked the immunosuppressive characteristics observed in patients, inducing a blunted phagocytic response and metabolic program associated with a tolerant state. Metabolic rewiring of the cells using a pharmacological inhibitor of glutamine synthetase, partially restored the phagocytic and inflammatory capacity of in vitro generated- as well as ACLF patient-derived monocytes. Highlighting its biological relevance, the glutamine synthetase/glutaminase ratio of ACLF patient-derived monocytes positively correlated with disease severity scores.ConclusionIn ACLF, monocytes feature a distinct transcriptional profile, polarised towards an immunotolerant state and altered metabolism. We demonstrated that metabolic rewiring of ACLF monocytes partially revives their function, opening up new options for therapeutic targeting in these patients.

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Role of Hepatitis E Virus Infection in Acute-on-Chronic Liver Failure

BioMed Research International ◽

10.1155/2018/9098535 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 9

Author(s):

Mario Frias ◽

Pedro López-López ◽

Antonio Rivero ◽

Antonio Rivero-Juarez

Keyword(s):

Liver Disease ◽

Liver Failure ◽

Hepatitis E Virus ◽

Hepatitis E ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Hepatic Decompensation ◽

End Stage ◽

The Impact

Chronic liver disease (CLD) with a variety of causes is currently reported to be one of the main causes of death worldwide. Patients with CLD experience deteriorating liver function and fibrosis, progressing to cirrhosis, chronic hepatic decompensation (CHD), end-stage liver disease (ESLD), and death. Patients may develop acute-on-chronic liver failure (ACLF), typically related to a precipitating event and associated with increased mortality. The objective of this review was to analyze the role of acute hepatitis E virus (HEV) infection in patients with CLD, focusing on the impact of this infection on patient survival and prognosis in several world regions.

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Uncertainty in the impact of liver support systems in acute-on-chronic liver failure: a systematic review and network meta-analysis

Annals of Intensive Care ◽

10.1186/s13613-020-00795-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Klementina Ocskay ◽

Anna Kanjo ◽

Noémi Gede ◽

Zsolt Szakács ◽

Gabriella Pár ◽

...

Keyword(s):

Liver Failure ◽

Support Systems ◽

Meta Analysis ◽

Statistical Significance ◽

Bioartificial Liver ◽

Chronic Liver ◽

Chronic Liver Failure ◽

Liver Support ◽

Bioartificial Liver Support ◽

The Impact

Abstract Background The role of artificial and bioartificial liver support systems in acute-on-chronic liver failure (ACLF) is still controversial. We aimed to perform the first network meta-analysis comparing and ranking different liver support systems and standard medical therapy (SMT) in patients with ACLF. Methods The study protocol was registered with PROSPERO (CRD42020155850). A systematic search was conducted in five databases. We conducted a Bayesian network meta-analysis of randomized controlled trials assessing the effect of artificial or bioartificial liver support systems on survival in patients with ACLF. Ranking was performed by calculating the surface under cumulative ranking (SUCRA) curve values. The RoB2 tool and a modified GRADE approach were used for the assessment of the risk of bias and quality of evidence (QE). Results In the quantitative synthesis 16 trials were included, using MARS®, Prometheus®, ELAD®, plasma exchange (PE) and BioLogic-DT®. Overall (OS) and transplant-free (TFS) survival were assessed at 1 and 3 months. PE significantly improved 3-month OS compared to SMT (RR 0.74, CrI: 0.6–0.94) and ranked first on the cumulative ranking curves for both OS outcomes (SUCRA: 86% at 3 months; 77% at 1 month) and 3-month TFS (SUCRA: 87%) and second after ELAD for 1-month TFS (SUCRA: 76%). Other comparisons did not reach statistical significance. QE was moderate for PE concerning 1-month OS and both TFS outcomes. Other results were of very low certainty. Conclusion PE seems to be the best currently available liver support therapy in ACLF regarding 3-month OS. Based on the low QE, randomized trials are needed to confirm our findings for already existing options and to introduce new devices.

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