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Transjugular intrahepatic portosystemic shunt (TIPS) may be used as a salvage treatment in patients with cirrhosis and refractory variceal bleeding. To synthesize the available evidence on the efficacy of TIPS in patients with cirrhosis and refractory variceal bleeding. Meta-analysis of trials evaluating TIPS in patients with cirrhosis and refractory variceal bleeding, including subgroup analysis to assess the impact of recent changes in the management of variceal bleeding (i.e., the use of Polytetrafluoroethylene-covered TIPS and the availability of pre-emptive TIPS as a first-line treatment for acute variceal bleeding). Twenty-three studies with 1430 patients were included. The pooled estimate rates were 0.33 (95% CI = 0.29-0.37) for death at 1 month-6 weeks, 0.46 (95% CI = 0.40-0.52) for death at 1 year, and 0.09 (95% CI = 0.06-0.11) for death due to rebleeding in the follow-up. The pooled estimate rates for death at 1 month or 6 weeks were similar in subgroup analyses including studies that did not use covered TIPS or that did not include patients after the pre-emptive TIPS area compared to the ones that did (pooled estimate rate 0.33 [95% CI = 0.28-0.38] and 0.32 [95% CI = 0.25-0.39], respectively). The pooled estimate rates were 0.16 (95% CI = 0.13-0.18) for rebleeding, 0.25 (95% CI = 0.17-0.36) for occurrence of hepatic encephalopathy, and 0.08 (95% CI = 0.05-0.13) for access to liver transplantation after TIPS insertion. One third of patients with cirrhosis and refractory variceal bleeding treated with salvage TIPS died within the first 6 weeks. Recent improvements in the management of variceal bleeding did not improve the survival of patients presenting with refractory variceal bleeding.

Background & Aims: Severe forms of alcohol-related liver disease are associated with increased susceptibility to infections which are associated with poor prognosis. The cellular and molecular mechanisms responsible for this altered host defense are incompletely understood. Methods: We performed whole blood phenotypic analysis and ex vivo stimulation with various pathogen-associated molecular patterns (PAMPs). We included 34 patients with alcohol-related cirrhosis (18 of whom had biopsy-proven severe alcoholic hepatitis [sAH]), 12 healthy controls and 11 patients with chronic alcohol consumption without significant liver disease. We also evaluated the transcriptomic (RNA-seq) and chromatin accessibility (ATAC-seq) profiles of CD14+ monocytes from a subset of patients. Results: Circulating monocytes and conventional dendritic cells (DCs) from patients with sAH displayed complex alterations characterized by increased expression of both activating and inhibitory surface markers and an impaired pro-inflammatory response upon stimulation with PAMPs representative of gram-negative bacteria (lipopolysaccharide, Pam3CSK4) or fungal pathogens (Zymosan). Their decreased ability to produce more than 1 cytokine (polyfunctionality) upon PAMP stimulation correlated with the risk of developing infection at 28 days or mortality at 90 days. The presence of acute-on-chronic liver failure in patients with sAH did not significantly modify the immune profile of monocytes and DCs. Moreover, CD14+ monocytes of patients with sAH displayed altered transcriptional and epigenomic profiles characterized by downregulation of key innate immune and metabolic pathways and upregulation of important immunomodulatory factors. Conclusions: In patients with sAH, the altered transcriptional program and functional properties of monocytes that contribute to patients' susceptibility to infection have strong epigenetic determinants. Lay summary: Patients with severe alcoholic hepatitis are at increased risk of infections, which contribute to the poor prognosis associated with the disease. Herein, we show that epigenetic determinants underly the immune cell dysfunction and inappropriate responses to pathogens that are associated with severe alcoholic hepatitis., SCOPUS: ar.j, info:eu-repo/semantics/published

In this review to the authors provide evidence-based definitions of organ failure in patients with acute decompensation of cirrhosis, describe the prevalence and prognostic impact of organ failure in these patients, and highlight current knowledge of the mechanisms responsible for its development. Excessive inflammatory response and a reduction of the capacity of organs to respond adequately to stress may sensitize cirrhotic patients to inflammation-driven organ damage and failure. The dynamic evolution of organ failure during early intensive management may provide a useful tool for guiding subsequent management strategies, or in some cases, for defining the futility of care. Currently, management of patients with acute-on-chronic liver failure is mainly supportive. Understanding the mechanisms of immunopathology and failed organ tolerance in acute decompensated cirrhosis could open new areas of research and define new therapeutic options in this life-threatening condition.

The constant renewal of the intestinal epithelium is fueled by intestinal stem cells (ISCs) lying at the base of crypts, and these ISCs continuously give rise to transit-amplifying progenitor cells during homeostasis. Upon injury and loss of ISCs, the epithelium has the ability to regenerate by the dedifferentiation of progenitor cells that then regain stemness and repopulate the pool of ISCs. Epithelial cells receive cues from immune cells, mesenchymal cells and the microbiome to maintain homeostasis. This review focuses on the response of the epithelium to damage and the interplay between the different intestinal compartments.

A better identification of factors predicting death is needed in alcoholic hepatitis (AH). Acute-on-chronic liver failure (ACLF) occurs during the course of liver disease and can be identified when AH is diagnosed (prevalent ACLF [pACLF]) or during follow-up (incidental ACLF [iACLF]). This study analyzed the impact of ACLF on outcomes in AH and the role of infection on the onset of ACLF and death.Patients admitted from July 2006 to July 2015 suffering from biopsy-proven severe (s)AH with a Maddrey discriminant function (mDF) ≥32 were included. Infectious episodes, ACLF, and mortality were assessed during a 168-day follow-up period. Results were validated on an independent cohort.One hundred sixty-five patients were included. Mean mDF was 66.3 ± 20.7 and mean model for end-stage liver disease score was 26.8 ± 7.4. The 28-day cumulative incidence of death (CID) was 31% (95% CI 24-39%). Seventy-nine patients (47.9%) had pACLF. The 28-day CID without pACLF and with pACLF-1, pACLF-2, and pACLF-3 were 10.4% (95% CI 5.1-18.0), 30.8% (95% CI 14.3-49.0), 58.3% (95% CI 35.6-75.5), and 72.4% (95% CI 51.3-85.5), respectively, p 0.0001. Twenty-nine patients (17.5%) developed iACLF. The 28-day relative risk of death in patients developing iACLF was 41.87 (95% CI 5.2-335.1; p 0.001). A previous infection was the only independent risk factor for developing iACLF during the follow-up. Prevalence, incidence, and impact on prognosis of ACLF were confirmed in a validation cohort of 97 patients with probable sAH.ACLF is frequent during the course of sAH and is associated with high mortality. Infection strongly predicts the development of ACLF in this setting.In patients with chronic liver disease, an acute deterioration of liver function combined with single or multiple organ failures is known as acute-on-chronic liver failure. This study shows that acute-on-chronic liver failure is frequent during the course of severe alcoholic hepatitis. In severe alcoholic hepatitis, acute-on-chronic liver failure is associated with high mortality and frequently occurs after an infection.

To determine the role of S100A8/A9 in the pathogenesis of primary Sjögren's syndrome (pSS).The serum levels of S100A8/A9 were determined in pSS patients and healthy controls by ELISA. The expression of S100A8/A9 in salivary glands was assessed by immunohistochemistry. The phenotype of S100A8+ and S100A9+ cells was identified using double immunofluorescence. The effects of S100A8/A9 on cytokine production by peripheral blood mononuclear cells (PBMCs) from pSS patients were determined in vitro by flow cytometry. The effects of pro-inflammatory cytokines on S100A8/A9 secretion were additionally investigated in vitro by ELISA in PBMCs from pSS patients and control subjects.Serum levels of S100A8/A9 were significantly increased in pSS patients compared to healthy controls. The tissular expression of S100A8 and S100A9, identified in professional phagocytes (neutrophils, monocytes and plasmacytoid dendritic cells), was increased in the salivary glands of pSS patients and correlated with focus score. In vitro, recombinant S100A8/A9 increased the production of IL-1β, IL-6, TNF-α, IFN-γ, IL-10, IL-17A and IL-22 by PBMCs. The S100A8/A9-induced increase in TNF-α production in pSS patients was significant relative to controls. Furthermore, IL-1β, TNF-α, IL-6, and IL-17A stimulated release of S100A8/A9 from PBMCs in pSS patients.S100A8/A9 is increased in pSS patients contributing to the in vitro increased production of pro-inflammatory cytokines. As such, S100A8/A9 in concert with other cytokines might contribute to the pathogenesis of pSS.

Background and objectives In 2009, the pandemic influenza A/H1N1 accounted for worldwide recommendations about vaccination. There are few data concerning the immunogenicity or the security of the adjuvanted-A/H1N1 vaccine in transplanted and hemodialyzed patients. Design, setting, participants, & measurements Sera from 21 controls, 53 hemodialyzed (HD) patients, and 111 renal transplant recipients (RT) were sampled before (T0) and 1 month after (T1) a single dose of Pandemrix (R) vaccine (GSK Biologicals, AS03-adjuvanted). We measured the neutralizing antibodies against A/H1N1/2009, the geometric mean (GM) titers, the GM titer ratios (T1/T0) with 95% confidence intervals, and the seroconversion rate (responders: >= 4-fold increase in titer). The HLA and MICA immunization was determined by Luminex technology. Results The GM titer ratio was 38 (19 to 78), 9 (5 to 16), and 5 (3 to 6) for controls, HD patients, and RI patients, respectively (P