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Project description:BACKGROUND/ AIMS: Severe forms of alcoholic liver disease are associated with increased susceptibility to infections largely due to immune dysfunction. In this study, we analyze the phenotypic, molecular and functional profiles of the mononuclear phagocyte system of patients with cirrhosis, severe alcoholic hepatitis (sAH) or acute-on-chronic liver failure (ACLF). RESULTS: sAH and ACLF patients display a severe impairment of the TH1-promoting IL-12p70/IFNgamma/CXCL10 axis. Furthermore, the CD14+ monocytes and classical dendritic cells of these patients are unable to mount an appropriate pro-inflammatory response after stimulation with PAMPs associated with gram-negative bacteria or fungal pathogens. These cells also have reduced polyfunctionality, which is associated with a higher risk of subsequent infection. Finally, we show that CD14+ monocytes of sAH and ACLF patients display a similar transcriptional profile characterized by immunosuppressive features. This was accompanied with changes in chromatin accessibility in enhancer regions of key immune and metabolic genes. CONCLUSIONS: Altered transcriptional program and functional properties of monocytes from sAH and ACLF patients has strong epigenetic determinants.
2020-08-02 | GSE135285 | GEO
Project description:BACKGROUND/ AIMS: Severe forms of alcoholic liver disease are associated with increased susceptibility to infections largely due to immune dysfunction. In this study, we analyze the phenotypic, molecular and functional profiles of the mononuclear phagocyte system of patients with cirrhosis, severe alcoholic hepatitis (sAH) or acute-on-chronic liver failure (ACLF). RESULTS: sAH and ACLF patients display a severe impairment of the TH1-promoting IL-12p70/IFNgamma/CXCL10 axis. Furthermore, the CD14+ monocytes and classical dendritic cells of these patients are unable to mount an appropriate pro-inflammatory response after stimulation with PAMPs associated with gram-negative bacteria or fungal pathogens. These cells also have reduced polyfunctionality, which is associated with a higher risk of subsequent infection. Finally, we show that CD14+ monocytes of sAH and ACLF patients display a similar transcriptional profile characterized by immunosuppressive features. This was accompanied with changes in chromatin accessibility in enhancer regions of key immune and metabolic genes. CONCLUSIONS: Altered transcriptional program and functional properties of monocytes from sAH and ACLF patients has strong epigenetic determinants.
2020-08-02 | GSE135284 | GEO
Project description:Epigenetic basis for monocyte dysfunction in acute-on-chronic liver failure and alcoholic hepatitis
| PRJNA558245 | ENA
Project description:Epigenetic basis for monocyte dysfunction in acute-on-chronic liver failure and alcoholic hepatitis [RNA-seq]
| PRJNA558250 | ENA
Project description:Epigenetic basis for monocyte dysfunction in acute-on-chronic liver failure and alcoholic hepatitis [ATAC-seq]
| PRJNA558249 | ENA
Project description:Acute alcoholic hepatitis (AAH) is a serious complication of alcohol misuse and has high short term mortality. It is a clinical syndrome characterised by jaundice and coagulopathy in a patient with a history of recent heavy alcohol use and is associated with profound immune dysfunction with a primed but ineffective immune response against pathogens. Here, we review the current knowledge of the pathogenesis and immune defects of AAH and identify areas requiring further study. Alcohol activates the immune system primarily through the disruption of gut tight junction integrity allowing the escape of pathogen-associated molecular particles (PAMPs) into the portal venous system. PAMPs stimulate cells expressing toll-like receptors (mainly myeloid derived cells) and initiate a network of intercellular signalling by secretion of many soluble mediators including cytokines and chemokines. The latter coordinates the infiltration of neutrophils, monocytes and T cells and results in hepatic stellate cell activation, cellular damage and hepatocyte death by necrosis or apoptosis. On the converse of this immune activation is the growing evidence of impaired microbial defence. Neutrophils have reduced phagocytic capacity and oxidative burst and there is recent evidence that T cell exhaustion plays a role in this.
| S-EPMC4641112 | biostudies-other
Project description:Non-alcoholic fatty liver disease (NAFLD) has become the most common liver disease worldwide. It is expected that non-alcoholic steatohepatitis (NASH), NASH-related cirrhosis and its decompensated forms will increase further in the next two decades. Acute-on-chronic liver failure (ACLF) is a distinct syndrome characterized by rapid deterioration of liver function in patients with chronic liver disease that is associated with development of one or more organ failures, and carries a very high short-term mortality. There is a paucity of data on ACLF in patients with NASH cirrhosis. Recent studies have shown that although ACLF incidence due to NASH is lower when compared to other etiologies, NASH is the fastest growing liver disease etiology among all ACLF hospitalizations. Higher rates of infections, as a precipitating factor, and circulatory failure were noted in this population. Metabolic derangements such as obesity and diabetes might also play a confounding role in the pathophysiology, clinical course, and prognosis of NASH patients with ACLF. Patients with ACLF due to NASH have shown a lower inpatient mortality despite a longer hospital length-of-stay and a higher 28- and 90-day mortality. Patients with ACLF should be promptly transferred to a transplant center and evaluated for liver transplantation (LT). Optimal prognostic scores, timing of LT, and the best bridge to LT therapy and treatment of post-LT complications need to be elucidated in prospective studies.
| S-EPMC7063516 | biostudies-literature
Project description:Background & aimsAlcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort.MethodsThis was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days.ResultsTwenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment.ConclusionsRifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients.
| S-EPMC9311407 | biostudies-literature
Project description:Acute-on-chronic liver failure (ACLF) is a complex syndrome that develops in patients with acutely decompensated cirrhosis. In this condition, dysbalanced immune function and excessive systemic inflammation are closely associated with organ failure and high short-term mortality. In this review, we describe how omic technologies have contributed to the characterization of the hyperinflammatory state in patients with acutely decompensated cirrhosis developing ACLF, with special emphasis on the role of metabolomics, lipidomics and transcriptomics in profiling the triggers (pathogen- and damage-associated molecular patterns [PAMPs and DAMPs]) and effector molecules (cytokines, chemokines, growth factors and bioactive lipid mediators) that lead to activation of the innate immune system. This review also describes how omic approaches can be invaluable tools to accelerate the identification of novel biomarkers that could guide the implementation of novel therapies/interventions aimed at protecting these patients from excessive systemic inflammation and organ failure.
| S-EPMC10197663 | biostudies-literature
Project description:Over the past 2 decades, the concept of acute-on-chronic liver failure (ACLF) has been proposed as an alternate path in the natural history of decompensated cirrhosis. ACLF thus is characterized by the presence of a precipitating event (identified or unidentified) in subjects with underlying chronic liver disease leading to rapid progression of liver injury and ending in multi-organ dysfunction characterized by high short-term mortality. Multiple organ failure and an increased risk for mortality are key to the diagnosis of ACLF. The prevalence of ACLF ranges from 24% to 40% in hospitalized patients. The pathophysiological basis of ACLF can be explained using the following 4-part model: predisposing event, injury caused by a precipitating event, response to injury, and organ failure. Although several mathematic scores have been proposed for identifying outcomes with ACLF, it is as yet unclear whether these organ failure scores are truly prognostic or only reflective of the dying process. Treatment paradigms continue to evolve but consist of early recognition, supportive intensive care, and consideration of liver transplantation before onset of irreversible multiple organ failure.
| S-EPMC4625547 | biostudies-literature