Effect of extracorporeal liver support by MARS and Prometheus on serum cytokines in acute-on-chronic liver failure

INTRODUCTION: Cytokines are believed to play an important role in acute-on-chronic liver failure (ACLF). Extracorporeal liver support systems may exert beneficial effects in ACLF via removal of cytokines. At present, two systems are commercially available, the Molecular Adsorbent Recirculating System (MARS™) and Fractionated Plasma Separation, Adsorption and Dialysis (Prometheus™). The aim of this study was to compare the effects of MARS and Prometheus treatments on serum cytokine levels and their clearances. METHODS: Eight patients with ACLF underwent alternating treatments with either MARS or Prometheus in a randomized cross-over design. Thirty-four treatments (17 MARS, 17 Prometheus) were available for analysis. Serum cytokines were measured before and after each treatment, and cytokine clearance was calculated from paired arterial and venous samples and effective plasma flow one hour after the start of treatment. RESULTS: Baseline serum levels of interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), and soluble TNF-α receptor 1 were significantly elevated in patients with ACLF. Measurable plasma clearances were detected for all cytokines tested, but no significant changes in serum levels of any cytokine were found after treatments with MARS or Prometheus. In MARS treatments, IL-10 was cleared from plasma more efficiently than IL-6. Clearance of IL-10 was higher in Prometheus than in MARS treatments. CONCLUSION: Cytokines are cleared from plasma by both MARS and Prometheus, but neither system is able to change serum cytokine levels. This discrepancy is probably due to a high rate of cytokine production in patients with ACLF

Liver Fibrosis-4 index indicates atrial fibrillation in acute ischemic stroke

BACKGROUND: Non-alcoholic fatty liver disease and particularly liver fibrosis is related to cardiovascular disease and may indicate an increased risk for atrial fibrillation (AF), but this association has not yet been systematically investigated in a cohort of ischemic stroke patients. METHODS: We analyzed data from a prospective single-center study enrolling all consecutive ischemic stroke patients admitted to our stroke unit over a one-year-period. All patients received a thorough etiological work-up. For evaluation of liver fibrosis, we determined the FIB-4 index, a well-established noninvasive liver fibrosis test. Laboratory results were analyzed from a uniform blood sample taken at stroke unit admission. RESULTS: Of 414 included patients (mean age 70.2 years, 57.7% male), FIB-4 indicated advanced liver fibrosis in 92 (22.2%). AF as the underlying stroke mechanism was present in 28.0% (large vessel disease: 25.6%, small vessel disease: 11.4%, cryptogenic: 29.2%). Patients with FIB-4 ≥2.67 had higher rates of AF (53.3% vs. 20.8%, p<0.001), this association remained significant after correction for established AF risk factors (Odds Ratio 2.53, 95% confidence interval 1.44-4.46, p=0.001). FIB-4 was further associated with worse functional outcome three months (p<0.001) and higher mortality four years post-stroke (p<0.02), but these relationships were no longer present after correction for age and initial stroke severity. Moreover, FIB-4 did not associate with long-term recurrent vascular events. CONCLUSIONS: Liver fibrosis assessed by the FIB-4 index is independently associated with AF in acute ischemic stroke patients. Further studies should evaluate whether adding the FIB-4 index to AF risk scores increases their precision

HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure

Abstract Background & Aims The occurrence of acute decompensation (AD) worsens the prognosis of advanced chronic liver disease (ACLD). Various insults leading to increased systemic inflammation trigger acute-on-chronic liver failure (ACLF) with dramatically increased short-term mortality. During acute conditions such as sepsis, high-density lipoprotein cholesterol (HDL-C) levels decrease rapidly and HDL particles undergo profound changes in their composition and function. Indices of HDL quantity and quality may therefore associate with progression and survival in patients with advanced liver disease. Methods We studied levels of HDL-cholesterol (HDL-C), its subclasses HDL2-C and HDL3-C, and apolipoprotein(apo)A-I as indices of HDL quantity and HDL cholesterol efflux capacity as a metric of HDL functionality in 508 patients with compensated or decompensated cirrhosis including ACLF and 40 age- and gender-matched controls. Results Baseline levels of HDL-C and apoA-I were significantly lower in stable cirrhosis compared to control and further decreased in AD and ACLF . In stable cirrhosis (n=228), both HDL-C and apoA-I predicted the development of liver-related complications independently of MELD. In patients with AD with or without ACLF (n=280) both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, high diagnostic accuracies for 90-day mortality in AD patients were found for HDL-C (AUROC 0.79 ) and apoA-I (AUROC 0.80 ), very similar to that of MELD (AUROC 0.81 ). On Kaplan-Meier analysis, HDL-C 17 mg/dl and apoA-I 50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to ACLD (AUROCs HDL-C: 0.81 vs. MELD: 0.77). Conclusion HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure

HDL-related biomarkers are robust predictors of survival in patients with chronic liver failure

Background & Aims: High-density lipoprotein cholesterol (HDL-C) levels are reduced in patients with chronic liver disease and inversely correlate with disease severity. During acute conditions such as sepsis, HDL-C levels decrease rapidly and HDL particles undergo profound changes in their composition and function. We aimed to determine whether indices of HDL quantity and quality associate with progression and survival in patients with advanced liver disease. Methods: HDL-related biomarkers were studied in 508 patients with compensated or decompensated cirrhosis (including acute-on-chronic liver failure [ACLF]) and 40 age- and gender-matched controls. Specifically, we studied levels of HDL-C, its subclasses HDL2-C and HDL3-C, and apolipoprotein A1 (apoA-I), as well as HDL cholesterol efflux capacity as a metric of HDL functionality. Results: Baseline levels of HDL-C and apoA-I were significantly lower in patients with stable cirrhosis compared to controls and were further decreased in patients with acute decompensation (AD) and ACLF. In stable cirrhosis (n = 228), both HDL-C and apoA-I predicted the development of liver-related complications independently of model for end-stage liver disease (MELD) score. In patients with AD, with or without ACLF (n = 280), both HDL-C and apoA-I were MELD-independent predictors of 90-day mortality. On ROC analysis, both HDL-C and apoA-I had high diagnostic accuracy for 90-day mortality in patients with AD (AUROCs of 0.79 and 0.80, respectively, similar to that of MELD 0.81). On Kaplan-Meier analysis, HDL-C <17 mg/dl and apoA-I <50 mg/dl indicated poor short-term survival. The prognostic accuracy of HDL-C was validated in a large external validation cohort of 985 patients with portal hypertension due to advanced chronic liver disease (AUROCs HDL-C: 0.81 vs. MELD: 0.77). Conclusion: HDL-related biomarkers are robust predictors of disease progression and survival in chronic liver failure

Efficacy of Albumin Treatment for Patients with Cirrhosis and Infections Unrelated to Spontaneous Bacterial Peritonitis

Background & aims: We performed a randomized trial to determine whether albumin should be administered to patients with infections unrelated to spontaneous bacterial peritonitis (SBP). Methods: We performed a multicenter, open-label trial in which 118 patients with cirrhosis, non-SBP infections, and additional risk factors for poor outcome were randomly assigned to receive antibiotics plus albumin (study group; n = 61) or antibiotics alone (control group; n = 57). The primary outcome was in-hospital mortality; secondary outcomes were effect of albumin on disease course. Results: There were no significant differences at baseline between groups in results from standard laboratory tests, serum markers of inflammation, circulatory dysfunction, or liver severity scores. However, the combined prevalence of acute on chronic liver failure (ACLF) and kidney dysfunction was significantly higher in the study group (44.3% vs 24.6% in the control group; P = .02), indicating greater baseline overall severity. There was no significant difference in the primary outcome between groups (13.1% in the study group vs 10.5% in the control group; P = .66). Circulatory and renal functions improved in only the study group. A significantly higher proportion of patients in the study group had resolution of ACLF (82.3% vs 33.3% in the control group; P = .03). A significantly lower proportion of patients in the study group developed nosocomial infections (6.6% vs 24.6% in the control group; P = .007). Conclusions: In a randomized trial of patients with advanced cirrhosis and non-SBP infections, in-hospital mortality was similar between those who received albumin plus antibiotics vs those who received only antibiotics (controls). However, patients given albumin were sicker at baseline and, during the follow-up period, a higher proportion had ACLF resolution and a lower proportion had nosocomial infections. ClinicalTrials.gov no: NCT02034279

Systemic inflammation in decompensated cirrhosis: Characterization and role in acute-on-chronic liver failure.

Acute‐on‐chronic liver failure (ACLF) in cirrhosis is characterized by acute decompensation (AD), organ failure(s), and high short‐term mortality. Recently, we have proposed (systemic inflammation [SI] hypothesis) that ACLF is the expression of an acute exacerbation of the SI already present in decompensated cirrhosis. This study was aimed at testing this hypothesis and included 522 patients with decompensated cirrhosis (237 with ACLF) and 40 healthy subjects. SI was assessed by measuring 29 cytokines and the redox state of circulating albumin (HNA2), a marker of systemic oxidative stress. Systemic circulatory dysfunction (SCD) was estimated by plasma renin (PRC) and copeptin (PCC) concentrations. Measurements were performed at enrollment (baseline) in all patients and sequentially during hospitalization in 255. The main findings of this study were: (1) Patients with AD without ACLF showed very high baseline levels of inflammatory cytokines, HNA2, PRC, and PCC. Patients with ACLF showed significantly higher levels of these markers than those without ACLF; (2) different cytokine profiles were identified according to the type of ACLF precipitating event (active alcoholism/acute alcoholic hepatitis, bacterial infection, and others); (3) severity of SI and frequency and severity of ACLF at enrollment were strongly associated. The course of SI and the course of ACLF (improvement, no change, or worsening) during hospitalization and short‐term mortality were also strongly associated; and (4) the strength of association of ACLF with SI was higher than with SCD. Conclusion: These data support SI as the primary driver of ACLF in cirrhosis

Іншомовні аспекти фахової між культурної комунікації в сучасній вітчизняній і зарубіжній науковій літературі

У статті розглядаються основні напрямки сучасних вітчизняних і зарубіжних наукових досліджень з іншомовної фахової міжкультурної комунікації. Aspects of the professional foreign language of intercultural communication in modern domestic and foreign scientific literature. The paper discusses the main directions of current domestic and foreign scientific research in the field of professional foreign language intercultural communication

Sepsid even-skipped enhancers are functionally conserved in Drosophila despite lack of sequence conservation

10.1371/journal.pgen.1000106PLoS Genetics46

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BACKGROUND: Histologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD. METHODS: This was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0-4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0-2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226. FINDINGS: Of 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44-63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33-91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62-0·81) for histology, 0·76 (0·70-0·83) for LSM-VCTE, 0·74 (0·64-0·82) for FIB-4, and 0·70 (0·63-0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression. INTERPRETATION: Simple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases. FUNDING: Innovative Medicines Initiative 2