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The pathophysiological background of decompensated cirrhosis is characterised by a systemic proinflammatory and pro-oxidant milieu that plays a major role in the development of multiorgan dysfunction. Such abnormality is mainly due to the systemic spread of bacteria and/or bacterial products from the gut and danger-associated molecular patterns from the diseased liver triggering the release of proinflammatory mediators by activating immune cells. The exacerbation of these processes underlies the development of acute-on-chronic liver failure. A further mechanism promoting multiorgan dysfunction and failure likely consists with a mitochondrial oxidative phosphorylation dysfunction responsible for systemic cellular energy crisis. The systemic proinflammatory and pro-oxidant state of patients with decompensated cirrhosis is also responsible for structural and functional changes in the albumin molecule, which spoil its pleiotropic non-oncotic properties such as antioxidant, scavenging, immune-modulating and endothelium protective functions. The knowledge of these abnormalities provides novel targets for mechanistic treatments. In this respect, the oncotic and non-oncotic properties of albumin make it a potential multitarget agent. This would expand the well-established indications to the use of albumin in decompensated cirrhosis, which mainly aim at improving effective volaemia or preventing its deterioration. Evidence has been recently provided that long-term albumin administration to patients with cirrhosis and ascites improves survival, prevents complications, eases the management of ascites and reduces hospitalisations. However, variant results indicate that further investigations are needed, aiming at confirming the beneficial effects of albumin, clarifying its optimal dosage and administration schedule and identify patients who would benefit most from long-term albumin administration.

The treatment of hepatitis C virus infection was associated with the development of a complete remission in a patient with follicular lymphoma. To the Editor: Here we describe a patient with advanced follicular lymphoma and concurrent hepatitis C virus (HCV) infection. The patient had complete remission of both conditions after treatment with direct-acting antiviral therapy (sofosbuvir) and ribavirin. In February 2014, a 44-year old man presented with submandibular swelling. A biopsy showed grade 2 follicular lymphoma that was positive for CD20, CD10, B-cell lymphoma 6 protein (BCL6), and B-cell lymphoma 2 protein (BCL2) with a Ki67 proliferation index of 15%. Stage 4 disease was diagnosed on the basis of widespread lymphadenopathy, a large mesenteric mass (Figure 1A) that measured 7.5 cm by . . .

The association between advanced liver disease and frailty has been widely documented and frailty itself is associated with an increased risk of cirrhosis progression and death.1 Indeed, patients on the liver transplant waiting list are encouraged to increase their physical activity prior to surgery. However, these represent the minority of liver disease patients. Naimimohasses et al2 in their well-conducted study using multiple assessment tools in this edition of BMJ Open Gastroenterology demonstrate that one-third of patients are frail and one-third ‘prefrail’ in early-stage non-alcoholic fatty liver disease (NAFLD), and that frailty is more frequently found in female patients. This high prevalence was unexpected, and the mean age of the cohort was relatively young at 56±12 years. These findings are important. Predictably frailty was more common in those with increased liver fibrosis.

Patients hospitalized with decompensated cirrhosis and a serum albumin level of less than 30 g per liter were randomly assigned to daily albumin infusions to raise the albumin level to 30 g per liter or higher or to standard care. Albumin infusions did not reduce the incidences of infection, kidney dysfunction, and death. More serious adverse events occurred in the albumin group.

In both studies, patients with compensated cirrhosis who had clinically significant portal hypertension, as determined directly by measurement of hepatic venous pressure gradient or indirectly by assessing for presence of varices, received either an NSBB (propranolol, carvedilol v placebo in the RCT, or carvedilol v either placebo or endoscopic variceal band ligation in the individual patient data meta-analysis). In the UK, direct measurement of hepatic venous pressure gradient, which was used to diagnose clinically significant portal hypertension in the RCT and in one of the trials within the individual patient data, is not undertaken in practice routinely. [...]the decision about whether a person is likely to have clinically significant portal hypertension remains a clinical one that might be informed by tests of liver stiffness, presence of collaterals or splenomegaly on ultrasound imaging, or biomarkers (for example, platelet count <150 or emerging tests such as osteopontin or Von Willebrand factor). [Recommendations based on low to moderate quality evidence from a randomised controlled trial and an individual patient data meta-analysis, economic modelling results, and on the committee’s experience and expertise] Preventing bleeding from varices Endoscopic band ligation remains the current standard practice for preventing bleeding from varices. An economic analysis developed for this guideline, based on the outcomes of the evidence review, found little difference between band ligation and NSBBs regarding the impact on quality of life as a result of averted variceal bleeds and early mortality.

Patients with cirrhosis are susceptible to infection, but the mechanisms underlying this immunosuppression remain unclear. Derek W. Gilroy and colleagues show that plasma prostaglandin E 2 (PGE 2 ) is elevated in these patients and in mouse models of liver injury and suppresses TNF-α release from macrophages. Albumin, which binds to PGE 2 and reduces its bioavailability, is reduced in the plasma of a subset of cirrhosis patients. Administration of albumin partially reverses the immunosuppression observed in vitro and restores bacterial killing in mouse models, suggesting that future studies are warranted on the use of albumin to prevent infection in a subset of patients with cirrhosis. Liver disease is one of the leading causes of death worldwide 1 . Patients with cirrhosis display an increased predisposition to and mortality from infection due to multimodal defects in the innate immune system 2 , 3 , 4 ; however, the causative mechanism has remained elusive. We present evidence that the cyclooxygenase (COX)-derived eicosanoid prostaglandin E 2 (PGE 2 ) drives cirrhosis-associated immunosuppression. We observed elevated circulating concentrations (more than seven times as high as in healthy volunteers) of PGE 2 in patients with acute decompensation of cirrhosis. Plasma from these and patients with end-stage liver disease (ESLD) suppressed macrophage proinflammatory cytokine secretion and bacterial killing in vitro in a PGE 2 -dependent manner via the prostanoid type E receptor-2 (EP2), effects not seen with plasma from patients with stable cirrhosis (Child-Pugh score grade A). Albumin, which reduces PGE 2 bioavailability, was decreased in the serum of patients with acute decompensation or ESLD (<30 mg/dl) and appears to have a role in modulating PGE 2 -mediated immune dysfunction. In vivo administration of human albumin solution to these patients significantly improved the plasma-induced impairment of macrophage proinflammatory cytokine production in vitro . Two mouse models of liver injury (bile duct ligation and carbon tetrachloride) also exhibited elevated PGE 2 , reduced circulating albumin concentrations and EP2-mediated immunosuppression. Treatment with COX inhibitors or albumin restored immune competence and survival following infection with group B Streptococcus . Taken together, human albumin solution infusions may be used to reduce circulating PGE 2 levels, attenuating immune suppression and reducing the risk of infection in patients with acutely decompensated cirrhosis or ESLD.

Purpose Patients with decompensated liver cirrhosis who are admitted to intensive care units (ICU) are perceived, within the UK, as having a particularly poor prognosis. Methods We performed a descriptive analysis of cirrhosis patients admitted to general critical care units 1995–2008 compared to patients admitted with pre-existing chronic renal failure. Data were obtained from the Intensive Care National Audit and Research Centre Case Mix Programme Database incorporating 192 adult critical care units in England, Wales and Northern Ireland. Results Cirrhosis accounted for 2.6 % (16,096 patients) of total admissions with mean age 52.5 years and male preponderance (~60 %). Hospital mortality was high (>55 %) although this improved 5 % in recent years, and median length of stay was short (2.5 days). Mortality in cirrhotics with severe sepsis requiring organ support was 65–90 %, compared to 33–39 % in those without. Conversely, patients with chronic renal failure had lower mortality (42 %) despite similar characteristics and higher acute physiology and chronic health evaluation (APACHE) II scores. The APACHE II score under-predicted mortality in cirrhotics. Conclusions Cirrhosis patients exhibit worse outcomes compared to pre-existing renal failure patients, despite similar characteristics. Survival worsens considerably with organ failure, especially with sepsis. They represent a small number of admissions, albeit increasing over recent years, and, in general, have a short ICU stay. Patients with single organ failure have acceptable survival rates and mortality has improved; although we have no data on those refused ICU admission potentially causing survival bias. Given the extremely high mortality in patients with multi-organ failure, support should be limited/withdrawn in such patients.

ObjectivesPatients with liver disease frequently require hospitalisation with infection often the trigger. Influenza vaccination is an effective infection prevention strategy in healthy and elderly but is often perceived less beneficial in patients with liver disease. We investigated whether influenza vaccination triggered serological response and prevented hospitalisation and death in liver disease.DesignSystematic review and meta-analysis.Data sourcesMEDLINE, EMBASE, PubMed and CENTRAL up to January 2019.Eligibility criteriaRandomised or observational studies of the effects of influenza vaccine in adults with liver disease.Data extraction and synthesisTwo reviewers screened studies, extracted data and assessed risk of bias and quality of evidence. Primary outcomes were all-cause hospitalisation and mortality. Secondary outcomes were cause-specific hospitalisation and mortality, and serological vaccine response. Random-effects meta-analysis was used to estimate pooled effects of vaccination.ResultsWe found 10 041 unique records, 286 were eligible for full-text review and 12 were included. Most patients had viral liver disease. All studies were of very low quality. Liver patients both with and without cirrhosis mounted an antibody response to influenza vaccination, and vaccination was associated with a reduction in risk of hospital admission from 205/1000 to 149/1000 (risk difference −0.06, 95% CI −0.07 to 0.04) in patients with viral liver disease. Vaccinated patients were 27% less likely to be admitted to hospital compared with unvaccinated patients (risk ratio 0.73, 95% CI 0.66 to 0.80). No effect against all-cause or cause-specific mortality or cause-specific hospitalisation was found.ConclusionsThe low quantity and quality of the evidence means that the protective vaccine effect may be uncertain. Considering the high risk of serious health outcomes from influenza infection in patients with liver disease and the safety and low cost of vaccination, overall, the potential benefits of seasonal vaccination both to patients and the healthcare systems are likely to outweigh the costs and risks associated with vaccination.PROSPERO registration numberCRD42017067277.

IntroductionPatients with advanced cirrhosis have enteric bacterial dysbiosis and translocation of bacteria and their products across the gut epithelial barrier. This culminates in systemic inflammation and endotoxaemia, inducing innate immune dysfunction which predisposes to infection, and development of complications such as bleeding, sepsis and hepatic encephalopathy. This feasibility study aims to assess the safety of administering faecal microbiota transplantion to patients with cirrhosis and explore the effect of the intervention on their prognosis by achieving restoration of a healthy gut microbiome.Methods and analysisA PROspective, randomised placebo controlled feasibility trial of Faecal mIcrobiota Transplantation is a single-centre, randomised, single-blinded, placebo-controlled study evaluating faecal microbiota transplantation (FMT) against placebo. Patients with advanced but stable cirrhosis with a Model for End-Stage Liver Disease score between 10 and 16 will be recruited. Twenty-four patients will be randomised to FMT plus standard of care (as per our institutional practice) and eight patients to placebo in a ratio of 3:1. Patients will be evaluated at baseline before the study intervention is administered and at 7, 30 and 90 days post-intervention to assess safety and adverse events. FMT/placebo will be administered into the jejunum within 7 days of baseline. The primary outcome measure will be safety and feasibility as assessed by recruitment rates, tolerability and safety of FMT treatment. Results will be disseminated via peer-reviewed journals and international conferences. The recruitment of the first patient occurred on 23 May 2018.Ethics and disseminationResearch Ethics approval was given by the London South East Research Ethics committee (ref 17/LO/2081).Trial registration numberNCT02862249 and EudraCT 2017-003629-13.