Acute-on-chronic liver failure: A distinct clinical syndrome

Journal of Hepatology, Journal Year: 2021, Volume and Issue: 75, P. S27 - S35

Published: May 23, 2021

Language: Английский

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Mitochondrial dysfunction governs immunometabolism in leukocytes of patients with acute-on-chronic liver failure

Journal of Hepatology, Journal Year: 2021, Volume and Issue: 76(1), P. 93 - 106

Published: Aug. 25, 2021

Patients with acute-on-chronic liver failure (ACLF) present a systemic hyperinflammatory response associated increased circulating levels of small-molecule metabolites. To investigate whether these alterations reflect inadequate cell energy output, we assessed mitochondrial morphology and central metabolic pathways emphasis on the tricarboxylic acid (TCA) cycle in peripheral leukocytes from patients acutely decompensated (AD) cirrhosis, without ACLF.The study included samples AD cirrhosis (108 128 ACLF) 41 healthy individuals. Leukocyte ultrastructure was visualized by transmission electron microscopy cytosolic fluxes were determined assessing NADH/FADH2 production various substrates. Plasma GDF15 FGF21 Luminex acylcarnitines LC-MS/MS. Gene expression analyzed RNA-sequencing PCR-based glucose metabolism profiler array.Mitochondrial advanced distinguished cristae rarefication swelling. The number mitochondria per leukocyte higher patients, accompanied reduction their size. Increased C6:0- C8:0-carnitine predicted mortality whereas strongly correlated gene set signature related to activation. Metabolic flux analyses revealed mononuclear preferential involvement extra-mitochondrial pathways, supported upregulated genes encoding enzymes glycolytic pentose phosphate pathways. In ACLF, function analysis uncovered break-points TCA at isocitrate dehydrogenase succinate level, which bridged anaplerotic reactions involving glutaminolysis nucleoside metabolism.Our findings provide evidence cellular, organelle biochemical that severe dysfunction governs immunometabolism ACLF.Patients stages disease have dismal prognosis due vital organ failures lack treatment options. this study, report functioning mitochondria, are known as powerhouse, is severely impaired probably consequence intense inflammation. Mitochondrial therefore hallmark disease.

Language: Английский

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Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes

Gut, Journal Year: 2020, Volume and Issue: 70(9), P. 1758 - 1767

Published: Nov. 16, 2020

Systemic inflammation promotes the development of clinical events in patients with advanced chronic liver disease (ACLD). We assessed whether (1) non-selective beta blocker (NSBB) treatment initiation impacts biomarkers systemic and (2) these changes predict complications mortality.Biomarkers inflammation, that is, white blood cell count (WBC), C reactive protein (CRP), interleukin-6 (IL-6) procalcitonin (PCT) were determined at sequential hepatic venous pressure gradient (HVPG) measurements without NSBB under stable intake. The influence NSBB-related on risk decompensation liver-related death was analysed using competing regression.Our study comprised 307 ACLD (Child-A: 77 (25.1%), Child-B: 161 (52.4%), Child-C: 69 (22.5%), median HVPG: 20 (IQR 17-24) mm Hg) including 231 (75.2%) decompensated disease.WBC significantly decreased upon therapy (median: -2 -19;+13)%, p=0.011) overall cohort. reductions WBC (Child-C: -16 (-30;+3)% vs (-16;+16)% Child-A: +3 (-7;+13)%, p<0.001) CRP -26 (-56,+8)% (-46;+13)% ±0 (-33;+33)%, more pronounced stages cirrhosis. NSBB-associated correlated (Spearman's ρ=0.228, p<0.001), PCT (ρ=0.470, p=0.002) IL-6 (ρ=0.501, p=0.001), but not HVPG (ρ=0.097, p=0.088).An decrease (ie, reduction ≥15%) achieved by n=91 (29.6%) found to be an independent protective factor further (subdistribution HR, sHR: 0.694 (0.49-0.98), p=0.038) mortality patient cohort (sHR: 0.561 (0.356-0.883), p=0.013).NSBB seems exert anti-inflammatory activity as evidenced levels. Interestingly, this effect most Child-C response. An ≥15% associated a death.

Language: Английский

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New clinical and pathophysiological perspectives defining the trajectory of cirrhosis

Journal of Hepatology, Journal Year: 2021, Volume and Issue: 75, P. S14 - S26

Published: May 23, 2021

Language: Английский

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Characterization of Blood Immune Cells in Patients With Decompensated Cirrhosis Including ACLF

Frontiers in Immunology, Journal Year: 2021, Volume and Issue: 11

Published: Feb. 5, 2021

Background and Aims Patients with cirrhosis 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 these patients. Material Methods Blood taken from 67 patients decompensated (including 35 critically ill ACLF intensive care unit), 12 healthy subjects, assigned either measurements clinical blood counts microarray (genomewide) analysis RNA expression whole-blood; neutrophils; or assessment neutrophil antimicrobial functions. Results Several features were found not those without ACLF. Indeed, count showed that characterized leukocytosis, neutrophilia, lymphopenia. Using CIBERSORT method deconvolute whole-blood RNA-expression data, revealed hallmark association neutrophilia increased proportions macrophages M0-like monocytes decreased memory lymphocytes (of B-cell, CD4 T-cell lineages), CD8 T cells natural killer cells. Microarray neutrophils had a unique phenotype including induction glycolysis granule genes, downregulation cell-migration cell-cycle genes. Moreover, defective production superoxide anion. Conclusions Genomic that, among cirrhosis, dysregulation immune cells, increases (that phenotype) monocytes, depletion several lymphocyte lymphocytes). All alterations, along anion production, may contribute immunosuppression ACLF, suggesting targets for future therapies.

Language: Английский

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