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As the global prevalence of chronic liver disease continues to rise, the need to determine which patients will develop end-stage liver disease and require liver transplantation is increasingly important. However, current prognostic models perform sub-optimally. We aim to determine microRNA profiles associated with clinical decompensation and mortality/transplantation within 1 year. We examined microRNA expression profiles in plasma samples from patients across the spectrum of cirrhosis (n = 154), acute liver failure (ALF) (n = 22), sepsis (n = 20) and healthy controls (HC) (n = 20). We demonstrated that a microRNA-based model (miR-24 and -27a) associated with systemic inflammation differentiated decompensated cirrhosis states from compensated cirrhosis and HC (AUC 0.77 (95% CI 0.69-0.85)). 6 patients within the compensated cirrhosis group decompensated the subsequent year and their exclusion improved model performance (AUC 0.81 (95% CI 0.71-0.89)). miR-191 (associated with liver injury) predicted risk of mortality across the cohort when acutely decompensated and acute-on-chronic-liver failure patients were included. When they were excluded miR-24 (associated with systemic inflammation) predicted risk of mortality. Our findings demonstrate that microRNA associated with systemic inflammation and liver injury predict adverse outcomes in cirrhosis. miR-24 and -191 require further investigation as prognostic biomarkers and therapeutic targets for patients with liver disease., (© 2024. The Author(s).)

Background: Immune dysfunction contributes to a high rate of infection in patients with acute decompensation of cirrhosis. CD52 is a glycoprotein prominently expressed in lymphocytes. Immune regulation by CD52 may be involved in adaptive immune dysfunction in cirrhosis. This study aimed to investigate the function of CD52 on CD4 + T cells on the blood of patients with acute decompensation of cirrhosis., Methods: The expression of CD52 in the peripheral blood lymphocytes of 49 patients with cirrhosis was investigated using flow cytometry and transcriptomics. Potential cis-membrane ligands of CD52 were discovered via proximity labelling followed by proteomics. The function of CD52 on antigen-specific activation of CD4 + T cells was examined using flow cytometry in CD52 CRISPR-Cas9 knockout primary T cells., Findings: CD52 expression was elevated in CD4 + T cells in acute decompensation of cirrhosis, and this elevation was correlated with increased disease severity and mortality. Components of the T cell receptor complex including TCRβ, CD3γ and CD3ε were identified and validated as cis-membrane ligands of CD52. Knockout of CD52 promoted antigen-specific activation, proliferation, and pro-inflammatory cytokine secretion., Interpretation: Membrane bound CD52 demonstrated cis-interaction with the T cell receptor and served as a dynamic regulator of antigen-specific activation of CD4 + T cells. The upregulation of CD52 in the periphery of acute decompensation of cirrhosis hinders the recognition of the T cell receptor by MHC, contributing to impaired T cell function. The development of an alternative anti-CD52 antibody is required to restore T cell function and prevent infections in cirrhosis., Funding: This study was supported by the NIHR Imperial Biomedical Research Centre, Institute for Translational Medicine and Therapeutics (P74713), Wellcome Trust (218304/Z/19/Z), and Medical Research Council (MR/X009904/1 and MR/R014019/1)., Competing Interests: Declaration of interests Authors disclose no conflicts., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: We aimed to assess the feasibility and reliability of sequential ultrasonographic and elastographic monitoring in acute liver failure (ALF)., Design: Observational study., Setting: ALF is a rare, life-threatening disease that requires intensive care admission and often liver transplant, where the accurate selection of patients is crucial. Liver elastography is a noninvasive tool that can measure hepatic stiffness, but previous results have been inconclusive in ALF., Patients: Patients admitted between October 2021 and March 2023 to the Liver Intensive Therapy Unit at King's College Hospital with ALF were recruited, with healthy control (HC) individuals and acute-on-chronic liver failure (ACLF) used as controls., Intervention: None., Measurements: Average shear wave velocity was recorded with ElastPQ on the right and left liver lobes and the spleen. Portal vein flow, hepatic artery resistive index, and peak systolic velocity were also recorded. Physiologic and histologic data were used for comparison., Main Results: Forty patients with ALF, 22 patients with ACLF, and 9 HC individuals were included in the study. At admission, liver stiffness measurement (LSM) of the right lobe was statistically different between HC individuals (5.6 ± 2 kPa), ALF (31.7 ± 17 kPa), and ACLF (76.3 ± 71 kPa) patients (ALF vs. ACLF, p = 0.0301). Spleen size and stiffness discriminated between ALF (10.4 ± 2 cm and 21.4 ± 16.6 kPa) and ACLF (14 ± 2.3 cm and 42.6 ± 26 kPa). At admission, LSM was not different between ALF patients who spontaneously survived versus patients who died or were transplanted in the following 90 days. However, the trend over the first 10 days of admission was different with a peak of LSM at day 5 in spontaneous survivors followed by reduction during the recovery phase. ALF patients with poor prognosis showed a persistently increased LSM., Conclusions: In ALF stiffness peaks at day 5 of admission with subsequent reduction in patients spontaneously surviving, showing significant difference according to the prognosis at day 7 of admission. LSM might be useful in distinguishing acute from acute-on-chronic liver failure together with spleen volume and stiffness., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine.)

Background & Aims: Acute liver failure (ALF) is a life-threatening disease characterised by high-grade inflammation and immunoparesis, which is associated with a high incidence of death from sepsis. Herein, we aimed to describe the metabolic dysregulation in ALF and determine whether systemic immune responses are modulated via the lysophosphatidylcholine (LPC)-autotaxin (ATX)-lysophosphatidylcholinic acid (LPA) pathway., Methods: Ninety-six individuals with ALF, 104 with cirrhosis, 31 with sepsis and 71 healthy controls (HCs) were recruited. Pathways of interest were identified by multivariate statistical analysis of proton nuclear magnetic resonance spectroscopy and untargeted ultraperformance liquid chromatography-mass spectrometry-based lipidomics. A targeted metabolomics panel was used for validation. Peripheral blood mononuclear cells were cultured with LPA 16:0, 18:0, 18:1, and their immune checkpoint surface expression was assessed by flow cytometry. Transcript-level expression of the LPA receptor (LPAR) in monocytes was investigated and the effect of LPAR antagonism was also examined in vitro., Results: LPC 16:0 was highly discriminant between ALF and HC. There was an increase in ATX and LPA in individuals with ALF compared to HCs and those with sepsis. LPCs 16:0, 18:0 and 18:1 were reduced in individuals with ALF and were associated with a poor prognosis. Treatment of monocytes with LPA 16:0 increased their PD-L1 expression and reduced CD155, CD163, MerTK levels, without affecting immune checkpoints on T and NK/CD56+T cells. LPAR1 and 3 antagonism in culture reversed the effect of LPA on monocyte expression of MerTK and CD163. MerTK and CD163, but not LPAR genes, were differentially expressed and upregulated in monocytes from individuals with ALF compared to controls., Conclusion: Reduced LPC levels are biomarkers of poor prognosis in individuals with ALF. The LPC-ATX-LPA axis appears to modulate innate immune response in ALF via LPAR1 and LPAR3. Further investigations are required to identify novel therapeutic agents targeting these receptors., Impact and Implications: We identified a metabolic signature of acute liver failure (ALF) and investigated the immunometabolic role of the lysophosphatidylcholine-autotaxin-lysophosphatidylcholinic acid pathway, with the aim of finding a mechanistic explanation for monocyte behaviour and identifying possible therapeutic targets (to modulate the systemic immune response in ALF). At present, no selective immune-based therapies exist. We were able to modulate the phenotype of monocytes in vitro and aim to extend these findings to murine models of ALF as a next step. Future therapies may be based on metabolic modulation; thus, the role of specific lipids in this pathway require elucidation and the relative merits of autotaxin inhibition, lysophosphatidylcholinic acid receptor blockade or lipid-based therapies need to be determined. Our findings begin to bridge this knowledge gap and the methods used herein could be useful in identifying therapeutic targets as part of an experimental medicine approach., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Aims: The clinical, prognostic, and therapeutic impact of adrenal insufficiency in acute liver failure (ALF) and acute-on-chronic liver failure (ACLF) remains controversial and exact diagnostic criteria are lacking. We sought to determine the diagnostic and therapeutic value of cortisol measurement and glucocorticoid (GC) treatment in ALF and ACLF., Methods: 28-day transplant-free survival (TFS) was studied in relation to absolute cortisol concentrations and to GC treatment in ALF (n = 30) and ACLF (n = 34) patients. Cortisol concentrations and short synacthen test were assessed by chemiluminescence immunoassay and liquid chromatography-mass spectrometry. Clinicians decided independently on GC treatment. In relation, phenotypic and functional characteristics of circulating monocytes were assessed., Results: In ALF, baseline cortisol concentrations <387 nmol/L predicted TFS (sensitivity 83%, specificity 53%). In ACLF, baseline cortisol <392 nmol/L correlated with TFS (sensitivity 80%, specificity 61%). In both, ALF and ACLF, GC treatment did not influence 28-day TFS in patients with low baseline cortisol. However, in patients with baseline cortisol exceeding 387 and 392 nmol/L, respectively, TFS was higher if they had been treated with GC. High baseline cortisol was associated with low HLA-DR expression on monocytes., Conclusion: Our data suggest a prognostic value of baseline cortisol measurement in ALF and ACLF. Overall, strong activation of the hypothalamic-pituitary-adrenal axis indicated poor prognosis. Furthermore, baseline cortisol deserves prospective evaluation as a guide for GC treatment decision-making., (© 2023 The Authors.)

Lipids are organic compounds insoluble in water with a variety of metabolic and non-metabolic functions. They not only represent an efficient energy substrate but can also act as key inflammatory and anti-inflammatory molecules as part of a network of soluble mediators at the interface of metabolism and the immune system. The role of endogenous bioactive lipid mediators has been demonstrated in several inflammatory diseases (rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, cancer). The liver is unique in providing balanced immunotolerance to the exposure of bacterial components from the gut transiting through the portal vein and the lymphatic system. This balance is abruptly deranged in liver failure syndromes such as acute liver failure and acute-on-chronic liver failure. In these syndromes, researchers have recently focused on bioactive lipid mediators by global metabonomic profiling and uncovered the pivotal role of these mediators in the immune dysfunction observed in liver failure syndromes explaining the high occurrence of sepsis and subsequent organ failure. Among endogenous bioactive lipids, the mechanistic actions of three classes (eicosanoids, pro-resolving lipid mediators and lysophospholipids) in the pathophysiological modulation of liver failure syndromes will be the topic of this narrative review. Furthermore, the therapeutic potential of lipid-immune pathways will be described., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Artru, McPhail, Triantafyllou and Trovato.)

Background & Aims: Rifaximin-α is efficacious for the prevention of recurrent hepatic encephalopathy (HE), but its mechanism of action remains unclear. We postulated that rifaximin-α reduces gut microbiota-derived endotoxemia and systemic inflammation, a known driver of HE., Methods: In a placebo-controlled, double-blind, mechanistic study, 38 patients with cirrhosis and HE were randomised 1:1 to receive either rifaximin-α (550 mg BID) or placebo for 90 days., Primary Outcome: 50% reduction in neutrophil oxidative burst (OB) at 30 days., Secondary Outcomes: changes in psychometric hepatic encephalopathy score (PHES) and neurocognitive functioning, shotgun metagenomic sequencing of saliva and faeces, plasma and faecal metabolic profiling, whole blood bacterial DNA quantification, neutrophil toll-like receptor (TLR)-2/4/9 expression and plasma/faecal cytokine analysis., Results: Patients were well-matched: median MELD (11 rifaximin-α vs. 10 placebo). Rifaximin-α did not lead to a 50% reduction in spontaneous neutrophil OB at 30 days compared to baseline (p = 0.48). However, HE grade normalised (p = 0.014) and PHES improved (p = 0.009) after 30 days on rifaximin-α. Rifaximin-α reduced circulating neutrophil TLR-4 expression on day 30 (p = 0.021) and plasma tumour necrosis factor-α (TNF-α) (p <0.001). Rifaximin-α suppressed oralisation of the gut, reducing levels of mucin-degrading sialidase-rich species, Streptococcus spp, Veillonella atypica and parvula, Akkermansia and Hungatella. Rifaximin-α promoted a TNF-α- and interleukin-17E-enriched intestinal microenvironment, augmenting antibacterial responses to invading pathobionts and promoting gut barrier repair. Those on rifaximin-α were less likely to develop infection (odds ratio 0.21; 95% CI 0.05-0.96)., Conclusion: Rifaximin-α led to resolution of overt and covert HE, reduced the likelihood of infection, reduced oralisation of the gut and attenuated systemic inflammation. Rifaximin-α plays a role in gut barrier repair, which could be the mechanism by which it ameliorates bacterial translocation and systemic endotoxemia in cirrhosis., Clinical Trial Number: ClinicalTrials.gov NCT02019784., Lay Summary: In this clinical trial, we examined the underlying mechanism of action of an antibiotic called rifaximin-α which has been shown to be an effective treatment for a complication of chronic liver disease which effects the brain (termed encephalopathy). We show that rifaximin-α suppresses gut bacteria that translocate from the mouth to the intestine and cause the intestinal wall to become leaky by breaking down the protective mucus barrier. This suppression resolves encephalopathy and reduces inflammation in the blood, preventing the development of infection., Competing Interests: Conflict of interest Dr V Patel and Ms A Zamalloa have delivered paid lectures for Norgine Pharmaceuticals Ltd. Professor Shawcross has participated in advisory boards for Norgine Pharmaceuticals Ltd, EnteroBiotix, Kaleido Biosciences, Mallinckrodt and Shionogi and has delivered paid lectures for Norgine Pharmaceuticals Ltd, Falk Pharma and Alfa Sigma. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality., Methods and Results: We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT-qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality., Conclusion: Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Purpose: Colorectal cancer (CRC) can be classified according to the chromosomal-instability pathway (a microsatellite-stable (MSS) pathway) and the microsatellite-instability (MSI) pathway. Adjuvant therapy after surgery in advanced CRC is usually based on fluoropyrimidine 5-fluorouracil (5-FU) alone or combined with other agents. Controversy however remains on the use of 5-FU-based regimens in treating MSI-related tumours., Aims: To systematically investigate the relationship between tumour microsatellite profile and 5-year overall survival in patients with CRC treated with 5-FU., Methods: A systematic literature review of PubMed and Embase databases was conducted. Pre-specified criteria determined study inclusion/exclusion. The PRISMA and QUADAS-2 criteria were used to assess study suitability and quality respectively. Patients were categorised as having either MSI or MSS CRC. Overall 5-year survival was estimated from Kaplan-Meier curves. Publication bias was assessed using funnel-plots and Egger's test., Results: 1807 studies were identified, with meta-analysis performed using nine studies. 5-FU treated individuals with CRC who died at 5 years were found to be 0.31 times less likely to have MSI than those who were alive, although this was not statistically significant. There was an insufficient number of studies to enable subgroup analysis by stage., Conclusions: In this meta-analysis, MSI status does not alter 5-year survival of patients with CRC patients treated with adjuvant 5-FU, however there is significant heterogeneity in the design of individual studies in the data synthesis. More studies are necessary to clarify whether CRC patients with MSI CRC, in particular early stage, should be offered 5-FU based adjuvant chemotherapy., (© 2021. The Author(s).)

Background & Aims: Acetaminophen (APAP)-induced acute liver failure (ALF) remains the most common cause of ALF in the Western world. Conventional prognostic models, utilising markers of liver injury and organ failure, lack sensitivity for mortality prediction. We previously identified a microRNA signature that is associated with successful regeneration post-auxiliary liver transplant and with recovery from APAP-ALF. Herein, we aimed to use this microRNA signature to develop outcome prediction models for APAP-ALF., Methods: We undertook a nested, case-control study using serum samples from 194 patients with APAP-ALF enrolled in the US ALF Study Group registry (1998-2014) at early (day 1-2) and late (day 3-5) time-points. A microRNA qPCR panel of 22 microRNAs was utilised to assess microRNA expression at both time-points. Multiple logistic regression was used to develop models which were compared to conventional prognostic models using the DeLong method., Results: Individual microRNAs confer limited prognostic value when utilised in isolation. However, incorporating them within microRNA-based outcome prediction models increases their clinical utility. Our early time-point model (AUC = 0.78, 95% CI 0.71-0.84) contained a microRNA signature associated with liver regeneration and our late time-point model (AUC = 0.83, 95% CI 0.76-0.89) contained a microRNA signature associated with cell-death. Both models were enhanced when combined with model for end-stage liver disease (MELD) score and vasopressor use and both outperformed the King's College criteria. The early time-point model combined with clinical parameters outperformed the ALF Study Group prognostic index and the MELD score., Conclusions: Our findings demonstrate that a regeneration-linked microRNA signature combined with readily available clinical parameters can outperform existing prognostic models for ALF in identifying patients with poor prognosis who may benefit from transplantation., Lay Summary: While acute liver failure can be reversible, some patients will die without a liver transplant. We show that blood test markers that measure the potential for liver recovery may help improve identification of patients unlikely to survive acute liver failure who may benefit from a liver transplant., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Gut dysbiosis and inflammation perpetuate loss of gut barrier integrity (GBI) and pathological bacterial translocation (BT) in cirrhosis, contributing to infection risk. Little is known about gut inflammation in cirrhosis and how this differs in acute decompensation (AD). We developed a novel approach to characterise intestinal immunopathology by quantifying faecal cytokines (FCs) and GBI markers., Methods: Faeces and plasma were obtained from patients with stable cirrhosis (SC; n = 16), AD (n = 47), and healthy controls (HCs; n = 31). A panel of 15 cytokines and GBI markers, including intestinal fatty-acid-binding protein-2 (FABP2), d-lactate, and faecal calprotectin (FCAL), were quantified by electrochemiluminescence/ELISA. Correlations between analytes and clinical metadata with univariate and multivariate analyses were performed., Results: Faecal (F) IL-1β, interferon gamma, tumour necrosis factor alpha, IL-21, IL-17A/F, and IL-22 were significantly elevated in AD vs. SC ( q <0.01). F-IL-23 was significantly elevated in AD vs. HC ( p  = 0.0007). FABP2/d-lactate were significantly increased in faeces in AD vs. SC and AD vs. HC ( p <0.0001) and in plasma ( p  = 0.0004; p  = 0.011). F-FABP2 correlated most strongly with disease severity (Spearman's rho: Child-Pugh 0.466; p <0.0001; model for end-stage liver disease 0.488; p <0.0001). FCAL correlated with plasma IL-21, IL-1β, and IL-17F only and none of the faecal analytes. F-cytokines and F-GBI markers were more accurate than plasma in discriminating AD from SC., Conclusions: FC profiling represents an innovative approach to investigating the localised intestinal cytokine micro-environment in cirrhosis. These data reveal that AD is associated with a highly inflamed and permeable gut barrier. FC profiles are very different from the classical innate-like features of systemic inflammation. There is non-specific upregulation of T H 1/T H 17 effector cytokines and those known to mediate intestinal barrier damage. This prevents mucosal healing in AD and further propagates BT and systemic inflammation., Lay Summary: The gut barrier is crucial in cirrhosis in preventing infection-causing bacteria that normally live in the gut from accessing the liver and other organs via the bloodstream. Herein, we characterised gut inflammation by measuring different markers in stool samples from patients at different stages of cirrhosis and comparing this to healthy people. These markers, when compared with equivalent markers usually measured in blood, were found to be very different in pattern and absolute levels, suggesting that there is significant gut inflammation in cirrhosis related to different immune system pathways to that seen outside of the gut. This provides new insights into gut-specific immune disturbances that predispose to complications of cirrhosis, and emphasises that a better understanding of the gut-liver axis is necessary to develop better targeted therapies., Competing Interests: None of the authors have any conflicts of interest to declare. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2020 The Author(s).)

Background: The development of delirium has been previously demonstrated to be associated with an increased risk of mortality and length of stay post liver transplant (LTx) with multiple risk factors being identified in previous studies. In this study, we have aimed to identify the most important variables associated with the onset of post-LTx delirium and understand the effect on length of stay (LOS)., Methods: All liver transplants for chronic liver disease between 1 August 2012 and 1 August 2017 were included (n = 793). Data were collected for analysis retrospectively from electronic patient records., Results: Delirium is associated with an overall increased hospital and ICU LOS but not one-year mortality. The risk of developing post-LTx delirium was the greatest among patients: with post-LTx sepsis, who required renal sparing immunosuppression, who received donation after cardiac death (DCD) grafts and who were older. Patients with autoimmune hepatitis, primary biliary cholangitis or primary sclerosing cholangitis seemed to be at lower risk of post-LTx delirium. However, global patient LOS was only prolonged in patients with sepsis and renal failure., Conclusion: Many of the risk factors previously described to be associated with the development of post-LTx delirium were not demonstrated to be significant in this study. Sepsis, renal failure, older age and DCD use are associated with delirium post-LTx. It is unclear if this syndrome is an independent risk factor for increased LOS or if it is a symptom of well established syndromes associated with increased LOS. The role for prophylactic strategies to reduce the incidence of post-LTx delirium is therefore unclear.

Background: In patients with cirrhosis, progression to acute decompensation (AD) and acute-on-chronic liver failure (ACLF) has been associated with poor prognosis. Differential leucocyte ratios might predict mortality in systemic inflammatory conditions., Aim: To evaluate differential leucocyte ratios as prognostic biomarkers in patients with cirrhosis., Methods: Patients with AD and ACLF were recruited from four centres in three countries. Peripheral blood differential leucocytes were measured (three centres using flow cytometry) on hospital admission and at 48 hours. Ratios were correlated to model for end-stage liver disease (MELD), chronic liver failure-sequential organ failure (CLIF-SOFA), suspected/culture-positive bacterial infection and survival., Results: Nine hundred twenty-six patients (562 (61%) male, median age 55 (25-94) years) were studied. Overall, 350 (37%) did not survive to hospital discharge. Neutrophil-lymphocyte ratio (NLR) and monocyte-lymphocyte ratio (MLR) were elevated in patients with AD and ACLF who died during their hospital stay. On multivariate analysis NLR retained statistical significance independently of CLIF-SOFA or MELD. NLR >30 was associated with an 80% 90-day mortality in patients with ACLF but not AD. On sensitivity analysis for subgroups (alcohol-related liver disease and suspected sepsis), NLR and MLR retained statistically robust accuracy for the prediction of mortality. Significant predictive accuracy was only observed in centres using flow cytometry., Conclusion: Leucocyte ratios are simple and robust biomarkers of outcome in ACLF, which are comparable to CLIF-SOFA score but dependent on leucocyte quantification method. NLR and MLR may be used as screening tools for mortality prediction in patients with acutely deteriorating cirrhosis., (© 2020 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

We previously demonstrated a distinct hepatic microRNA (miRNA) signature (down-regulation of miRNA-23a, -150, - 200b, -503, and -663 and up-regulation of miRNA-20a) is associated with successful regeneration in auxiliary liver transplantation (ALT). This study aimed to evaluate whether the serum expression of this regeneration-linked miRNA signature is associated with clinical outcomes in acute and chronic liver disease. These were represented by patients with acetaminophen-induced acute liver failure (ALF; n = 18) and patients with hepatitis C virus (HCV) undergoing treatment with direct-acting antivirals (n = 56), respectively. Patients were grouped depending on their clinical outcome. Global serum miRNA expression was analyzed using polymerase chain reaction (PCR) arrays and selected miRNA expression using targeted PCR. We demonstrate that specific regeneration-linked miRNAs discriminate outcomes in both clinical scenarios. We further show that miRNA-20a, -23a, -150, -200b, -503, and -663 undergo concordant changes in expression in 3 distinct clinical settings: liver regeneration accompanying successful ALT, clinical recovery after ALF, and clinical recompensation after cure of HCV. This miRNA signature represents a potentially novel biomarker to predict outcome and optimize patient selection for liver transplantation in both acute and chronic liver disease., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

The metabolic response to endotoxemia closely mimics those seen in sepsis. Here, we show that the urinary excretion of the metabolite 2-hydroxyglutarate (2HG) is dramatically suppressed following lipopolysaccharide (LPS) administration in vivo , and in human septic patients. We further show that enhanced activation of the enzymes responsible for 2-HG degradation, D- and L-2-HGDH, underlie this effect. To determine the role of supplementation with 2HG, we carried out co-administration of LPS and 2HG. This co-administration in mice modulates a number of aspects of physiological responses to LPS, and in particular, protects against LPS-induced hypothermia. Our results identify a novel role for 2HG in endotoxemia pathophysiology, and suggest that this metabolite may be a critical diagnostic and therapeutic target for sepsis., (Copyright © 2020 Fitzpatrick, Lambden, Macias, Puthucheary, Pietsch, Mendil, McPhail and Johnson.)

Objective: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival., Materials and Methods: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality., Results: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) μg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival., Conclusions: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.

Purpose of Review: This review describes the current intensive care management of acute liver failure (ALF) and the latest evidence for emerging therapies., Recent Findings: Mortality from ALF continues to improve and in some cases, medical therapy can negate the need for liver transplantation because of protocolized management in specialist centres. Liver transplantation remains the cornerstone of management for poor prognosis ALF. The reduced use of blood products in ALF reflects growing evidence of balanced haemostasis in severe liver disease. Prophylactic therapeutic hypothermia is no longer recommended for neuroprotection. In cases not suitable for liver transplantation, high-volume plasma exchange (HVP) has potential benefit, although further research on the optimal timing and dosing is needed. Although sepsis remains an important complication in ALF, the use of prophylactic antimicrobials is being questioned in the era of emerging bacterial resistance., Summary: ICU management of ALF has improved such that liver transplantation is not required in some cases. HVP has emerged as a potential therapy for patients who may not be good liver transplantation candidates. Nevertheless in suitable patients with poor prognosis liver transplantation remains the optimal therapy.

This manuscript represents an appraisal of the evidence in support of L-ornithine-L-aspartate (LOLA) for the management and treatment of hepatic encephalopathy (HE) in cirrhosis. Meta-analyses of randomized controlled trials (RCTs) conducted over the last two decades generally reveal evidence of benefit of LOLA in a range of clinical presentations. This included improvement of mental state grade in overt HE (OHE) assessed by West Haven criteria as well as in minimal HE (MHE) assessed by psychometric testing where the oral formulation of LOLA was determined to be particularly effective. However, concerns over study quality were noted in one meta-analysis. Nevertheless, the concomitant lowering of fasting blood ammonia was reported in all RCTs using this endpoint. Network meta-analyses showed that LOLA appears to be comparable (or superior) in efficacy to non-absorbable disaccharides or probiotics. Emerging evidence from single RCTs show efficacy of LOLA for the treatment of post-transjugular intrahepatic portosystemic shunt (TIPSS) HE as well as for secondary HE prophylaxis. These findings provide support for the use of LOLA in the treatment of HE and future trials should focus on the use of LOLA for prophylaxis.

Acute and acute-on-chronic liver failure (ALF and ACLF), though distinct clinical entities, are considered syndromes of innate immune dysfunction. Patients with ALF and ACLF display evidence of a pro-inflammatory state with local liver inflammation, features of systemic inflammatory response syndrome (SIRS) and vascular endothelial dysfunction that drive progression to multi-organ failure. In an apparent paradox, these patients are concurrently immunosuppressed, exhibiting acquired immune defects that render them highly susceptible to infections. This paradigm of tissue injury succeeded by immunosuppression is seen in other inflammatory conditions such as sepsis, which share poor outcomes and infective complications that account for high morbidity and mortality. Monocyte and macrophage dysfunction are central to disease progression of ALF and ACLF. Activation of liver-resident macrophages (Kupffer cells) by pathogen and damage associated molecular patterns leads to the recruitment of innate effector cells to the injured liver. Early monocyte infiltration may contribute to local tissue destruction during the propagation phase and results in secretion of pro-inflammatory cytokines that drive SIRS. In the hepatic microenvironment, recruited monocytes mature into macrophages following local reprogramming so as to promote resolution responses in a drive to maintain tissue integrity. Intra-hepatic events may affect circulating monocytes through spill over of soluble mediators and exposure to apoptotic cell debris during passage through the liver. Hence, peripheral monocytes show numerous acquired defects in acute liver failure syndromes that impair their anti-microbial programmes and contribute to enhanced susceptibility to sepsis. This review will highlight the cellular and molecular mechanisms by which monocytes and macrophages contribute to the pathophysiology of ALF and ACLF, considering both hepatic inflammation and systemic immunosuppression. We identify areas for further research and potential targets for immune-based therapies to treat these devastating conditions.

Objectives: To characterise the sketetal muscle metabolic phenotype during early critical illness., Methods: Vastus lateralis muscle biopsies and serum samples (days 1 and 7) were obtained from 63 intensive care patients (59% male, 54.7±18.0 years, Acute Physiology and Chronic Health Evaluation II score 23.5±6.5)., Measurements and Main Results: From day 1 to 7, there was a reduction in mitochondrial beta-oxidation enzyme concentrations, mitochondrial biogenesis markers (PGC1α messenger mRNA expression (-27.4CN (95% CI -123.9 to 14.3); n=23; p=0.025) and mitochondrial DNA copy number (-1859CN (IQR -5557-1325); n=35; p=0.032). Intramuscular ATP content was reduced compared tocompared with controls on day 1 (17.7mmol/kg /dry weight (dw) (95% CI 15.3 to 20.0) vs. 21.7 mmol/kg /dw (95% CI 20.4 to 22.9); p<0.001) and decreased over 7 days (-4.8 mmol/kg dw (IQR -8.0-1.2); n=33; p=0.001). In addition, the ratio of phosphorylated:total AMP-K (the bioenergetic sensor) increased (0.52 (IQR -0.09-2.6); n=31; p<0.001). There was an increase in intramuscular phosphocholine (847.2AU (IQR 232.5-1672); n=15; p=0.022), intramuscular tumour necrosis factor receptor 1 (0.66 µg (IQR -0.44-3.33); n=29; p=0.041) and IL-10 (13.6 ng (IQR 3.4-39.0); n=29; p=0.004). Serum adiponectin (10.3 µg (95% CI 6.8 to 13.7); p<0.001) and ghrelin (16.0 ng/mL (IQR -7-100); p=0.028) increased. Network analysis revealed a close and direct relationship between bioenergetic impairment and reduction in muscle mass and between intramuscular inflammation and impaired anabolic signaling. ATP content and muscle mass were unrelated to lipids delivered., Conclusions: Decreased mitochondrial biogenesis and dysregulated lipid oxidation contribute to compromised skeletal muscle bioenergetic status. In addition, intramuscular inflammation was associated with impaired anabolic recovery with lipid delivery observed as bioenergetically inert. Future clinical work will focus on these key areas to ameliorate acute skeletal muscle wasting., Trial Registration Number: NCT01106300., Competing Interests: Competing interests: ZAP has received consultancy fees from Lyric Pharmaceuticals, and attended Specialist Advisory Boards for GlaxoSmithKline and Fresenius Kabi. Other authors have no competing interest to declare., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background/objectives: l-Ornithine l-Aspartate (LOLA) is a mixture of two endogenous amino acids with the capacity to fix ammonia in the form of urea and/or glutamine. Its' efficacy for the treatment of Hepatic Encephalopathy (HE), a known hyperammonemic disorder, remains the subject of debate. This study quantitatively analyzed the efficacy of LOLA in patients with cirrhosis and HE., Methods: Efficacy was defined as the extent of lowering of blood ammonia and improvement of mental state assessed in clinically overt HE (OHE) by Westhaven criteria or psychometric testing for assessment of Minimal HE (MHE). Appropriate keywords were used for electronic and/or manual searches of databases to identify RCTs for inclusion. Study quality and risk of bias were assessed using the Jadad Composite Scale together with The Cochrane Scoring Tool. Random Effects Models were used to express pooled Risk Ratio (RR) or Mean Difference (MD) with associated 95% Confidence Intervals (CI)., Results: 10 RCTs (884 patients) were included. Regression analysis showed no evidence of publication bias or other small study effects. Eight RCTs had low risk of bias by Jadad/Cochrane criteria. Comparison with placebo/no intervention controls revealed that LOLA was significantly more effective for improvement of mental state in all types of HE (RR 1.36 (95% CI 1.10-1.69), p  = 0.005), OHE (RR: 1.19, 95% CI of 1.01-1.39, test for overall effect: Z  = 2.14, p  = 0.03), MHE (RR: 2.15 (1.48-3.14), p  < 0.0001) and for lowering of blood ammonia (MD: -17.50 μmol/l (-27.73 to (-7.26)), p  = 0.0008). Improvement of mental state was greater in trials with low risk of bias. Heterogeneity was reduced in trials from Europe or with >100 participants. Oral LOLA appeared particularly effective for the treatment of MHE., Conclusion: LOLA appears to improve mental state and lower ammonia in patients with HE or MHE. Further studies are required in some subgroups of HE and in the era of HE reclassification.

Objective: To assess the epidemiology and outcome of patients with cirrhosis following critical care unit admission., Design: Retrospective cohort study., Setting: Critical care units in England, Wales, and Northern Ireland participating in the U.K. Intensive Care National Audit and Research Centre Case Mix Programme., Patients: Thirty-one thousand three hundred sixty-three patients with cirrhosis identified of 1,168,650 total critical care unit admissions (2.7%) admitted to U.K. critical care units between 1998 and 2012., Interventions: None., Measurements and Main Results: Ten thousand nine hundred thirty-six patients had alcohol-related liver disease (35%). In total, 1.6% of critical care unit admissions in 1998 had cirrhosis rising to 3.1% in 2012. The crude critical care unit mortality of patients with cirrhosis was 41% in 1998 falling to 31% in 2012 (p < 0.001). Crude hospital mortality fell from 58% to 46% over the study period (p < 0.001). Mean(SD) Acute Physiology and Chronic Health Evaluation II score in 1998 was 20.3 (8.5) and 19.5 (7.1) in 2012. Mean Acute Physiology and Chronic Health Evaluation II score for patients with alcohol-related liver disease in 2012 was 20.6 (7.0) and 19.0 (7.2) for non-alcohol-related liver disease (p < 0.001). In adjusted analysis, alcohol-related liver disease was associated with increased risk of death (odds ratio, 1.51 [95% CI, 1.42-1.62; p < 0.001]) with a year-on-year reduction in hospital mortality (adjusted odds ratio, 0.95/yr, [0.94-0.96, p < 0.001])., Conclusions: More patients with cirrhosis are being admitted to critical care units but with increasing survival rates. Patients with alcohol-related liver disease have reduced survival rates partly explained by higher levels of organ failure at admission. Patients with cirrhosis and organ failure warrant a trial of organ support and universal prognostic pessimism is not justified.

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000-2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889-0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634-0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789-0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624-0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776-0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal)., (© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background & Aims: Predicting survival in decompensated cirrhosis (DC) is important in decision making for liver transplantation and resource allocation. We investigated whether high-resolution metabolic profiling can determine a metabolic phenotype associated with 90-day survival., Methods: Two hundred and forty-eight subjects underwent plasma metabotyping by (1)H nuclear magnetic resonance (NMR) spectroscopy and reversed-phase ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry (UPLC-TOF-MS; DC: 80-derivation set, 101-validation; stable cirrhosis (CLD) 20 and 47 healthy controls (HC))., Results: (1)H NMR metabotyping accurately discriminated between surviving and non-surviving patients with DC. The NMR plasma profiles of non-survivors were attributed to reduced phosphatidylcholines and lipid resonances, with increased lactate, tyrosine, methionine and phenylalanine signal intensities. This was confirmed on external validation (area under the receiver operating curve [AUROC]=0.96 (95% CI 0.90-1.00, sensitivity 98%, specificity 89%). UPLC-TOF-MS confirmed that lysophosphatidylcholines and phosphatidylcholines [LPC/PC] were downregulated in non-survivors (UPLC-TOF-MS profiles AUROC of 0.94 (95% CI 0.89-0.98, sensitivity 100%, specificity 85% [positive ion detection])). LPC concentrations negatively correlated with circulating markers of cell death (M30 and M65) levels in DC. Histological examination of liver tissue from DC patients confirmed increased hepatocyte cell death compared to controls. Cross liver sampling at time of liver transplantation demonstrated that hepatic endothelial beds are a source of increased circulating total cytokeratin-18 in DC., Conclusion: Plasma metabotyping accurately predicts mortality in DC. LPC and amino acid dysregulation is associated with increased mortality and severity of disease reflecting hepatocyte cell death., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Purpose: To develop a liver function-related risk prediction tool to identify acute-on-chronic liver failure patients at greatest risk of in-hospital mortality., Methods: The LiFe (liver, injury, failure, evaluation) score, was constructed based on the opinions of 157 intensivists within the European Society for Intensive Care Medicine. Experts were surveyed and instructed to weigh the diagnostic importance of each feature of a proposed prediction model. We performed a retrospective cohort study of 1916 patients with chronic liver disease admitted to a medical or surgical ICU between 1997, and 2011 in three large hospitals in Boston, USA, and London, UK, with arterial lactate, total bilirubin and INR drawn at ICU admission. The derivation cohort consisted of ICU patients from Brigham and Women's Hospital and Massachusetts General Hospital in Boston (n = 945), and the validation cohort comprised patients from Kings College Hospital, London, admitted to the Liver Intensive Therapy Unit (n = 971). A clinical prediction model was derived and validated based on a logistic regression model describing the risk of in-hospital mortality as a function of the predictors (arterial lactate 0-1.9, ≥2.0-3.9, ≥4.0-5.9, ≥6.0 mg/dL; total bilirubin 0-1.9, ≥2.0-3.9, ≥4.0-5.9, ≥6.0 mg/dL; INR 0-1.9, ≥2.0-3.9, ≥4.0-5.9, ≥6.0) at ICU admission. Performance analysis of the LiFe score against SOFA, CLIF-SOFA, APACHE II and SAPS II was completed in the validation cohort of critically ill cirrhotic patients., Results: The derivation cohort (n = 941) was 53% male with a mean age of 65 years and an in-hospital mortality rate of 30%. The validation cohort (n = 971) was 63% male with mean age of 51 years and an in-hospital mortality rate of 52%. The C statistic for the prediction model was 0.74 (95% CI 0.70-0.77) in the derivation cohort and 0.77 (95% CI 0.74-0.80) in the validation cohort. In the validation cohort, in-hospital mortality was 17% in the low-risk group (0 risk score points), 28% in the intermediate-risk group (1-3 points), 47% in the high-risk group (4-8 points), and 77% in the very high-risk group (>8 points). In the validation cohort, the C statistics for SOFA, CLIF-SOFA, APACHE II, and SAPS II were 0.80, 0.81, 0.77, and 0.78, respectively. Further, a significant positive correlation exists between LiFe score and acute-on-chronic liver failure grade, (r = 0.478, P < 0.001)., Conclusions: Our LiFe score calculated from arterial lactate, total bilirubin and INR at ICU admission is a simple, quick and easily understandable score that may increase clinical utility for risk prediction in ICU patients with acute-on-chronic liver failure. The LiFe score can be used in place of physiological based scores for early risk prediction in patients with chronic liver disease but is not intended to replace CLIF-SOFA as a benchmark for prognostication.

Background & Aims: The incidence of cirrhosis and subsequent development of organ dysfunction (OD) requiring intensive care unit (ICU) support is rising. Historically, critically ill cirrhotics are perceived as having poor prognosis and substantial cost of care., Methods: The aim was to prospectively analyse resource utilisation and cost of a large cohort of patients (n=660) admitted to a Liver ICU from 2000 to 2007 with cirrhosis and OD. Child Pugh, MELD, SOFA, APACHE II, and organ support requirements were collected. The Therapeutic Intervention Scoring System (TISS) score, a validated tool for estimating cost in ICU, was calculated daily. Logistic regression was used to determine independent predictors of increased cost., Results: Alcohol was the most common etiology (47%) and variceal bleeding (VB) the most common reason for admission (35%). Invasive ventilatory support was required in 74% of cases, vasopressors in 49%, and 50% required renal replacement therapy. Forty-nine per cent of non-transplanted patients survived to ICU discharge. Median TISS score and ICU cost per patient were 261 and €14,139, respectively. VB patients had the highest survival rates (53% vs. 24%; p<0.001) and lower associated cost. A combination of VB (OR 0.48), need for ventilation (OR 2.81), low PO(2)/FiO(2) on admission (OR 0.97), and lactate (OR 0.93) improved cost prediction on multivariate analysis (AUROC 0.7; p<0.001) but organ failure scores per se were poor predictors of cost., Conclusions: Patients with cirrhosis and OD result in considerable resource expenditure but have acceptable hospital survival. Further health economic assessment and outcome prediction tools are required to appropriately target resource utilisation., (Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)