Abstract
Background and AimsPatients with cirrhosis and acute-on-chronic liver failure (ACLF) have immunosuppression, indicated by an increase in circulating immune-deficient monocytes. The aim of this study was to investigate simultaneously the major blood-immune cell subsets in these patients.Material and MethodsBlood taken from 67 patients with decompensated cirrhosis (including 35 critically ill with ACLF in the intensive care unit), and 12 healthy subjects, was assigned to either measurements of clinical blood counts and microarray (genomewide) analysis of RNA expression in whole-blood; microarray (genomewide) analysis of RNA expression in blood neutrophils; or assessment of neutrophil antimicrobial functions.ResultsSeveral features were found in patients with ACLF and not in those without ACLF. Indeed, clinical blood count measurements showed that patients with ACLF were characterized by leukocytosis, neutrophilia, and lymphopenia. Using the CIBERSORT method to deconvolute the whole-blood RNA-expression data, revealed that the hallmark of ACLF was the association of neutrophilia with increased proportions of macrophages M0-like monocytes and decreased proportions of memory lymphocytes (of B-cell, CD4 T-cell lineages), CD8 T cells and natural killer cells. Microarray analysis of neutrophil RNA expression revealed that neutrophils from patients with ACLF had a unique phenotype including induction of glycolysis and granule genes, and downregulation of cell-migration and cell-cycle genes. Moreover, neutrophils from these patients had defective production of the antimicrobial superoxide anion.ConclusionsGenomic analysis revealed that, among patients with decompensated cirrhosis, those with ACLF were characterized by dysregulation of blood immune cells, including increases in neutrophils (that had a unique phenotype) and macrophages M0-like monocytes, and depletion of several lymphocyte subsets (including memory lymphocytes). All these lymphocyte alterations, along with defective neutrophil superoxide anion production, may contribute to immunosuppression in ACLF, suggesting targets for future therapies.
Highlights
Acute-on-chronic liver failure (ACLF), which develops in patients with acutely decompensated cirrhosis, is characterized by the existence of organ failure(s) and high in-hospital mortality [1, 2]
Clinical complete blood counts obtained on admission in the 31 French patients with cirrhosis showed that ACLF was characterized by significant increases in white-cell count, differential and absolute neutrophil counts, and significant decreases in differential lymphocyte count, as compared with the two other groups (AC and acute decompensation (AD)) (Figure 1A, Figure S1)
No significant differences in blood counts were seen between advanced cirrhosis (AC) and AD
Summary
Acute-on-chronic liver failure (ACLF), which develops in patients with acutely decompensated cirrhosis, is characterized by the existence of organ failure(s) and high in-hospital mortality [1, 2]. ACLF is associated with systemic inflammation as indicated by blood leukocytosis [1, 2], and high plasma levels of C-reactive protein [1, 2] and cytokines and chemokines [3, 4]. ACLF is characterised by systemic inflammation which is known to be energetically expensive and may skew nutrients otherwise required for other metabolic processes towards immune cells. This would deny peripheral organs the required nutrients which may result in systemic organ failure [6]. The aim of this study was to investigate simultaneously the major bloodimmune cell subsets in these patients
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