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Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible.

Acute-on-chronic liver failure combines an acute deterioration in liver function in an individual with pre-existing chronic liver disease and hepatic and extrahepatic organ failures, and is associated with substantial short-term mortality. Common precipitants include bacterial and viral infections, alcoholic hepatitis, and surgery, but in more than 40% of patients, no precipitating event is identified. Systemic inflammation and susceptibility to infection are characteristic pathophysiological features. A new diagnostic score, the Chronic Liver Failure Consortium (CLIF-C) organ failure score, has been developed for classification and prognostic assessment of patients with acute-on-chronic liver failure. Disease can be reversed in many patients, and thus clinical management focuses upon the identification and treatment of the precipitant while providing multiorgan-supportive care that addresses the complex pattern of physiological disturbance in critically ill patients with liver disease. Liver transplantation is a highly effective intervention in some specific cases, but recipient identification, organ availability, timing of transplantation, and high resource use are barriers to more widespread application. Recognition of acute-on-chronic liver failure as a clinically and pathophysiologically distinct syndrome with defined diagnostic and prognostic criteria will help to encourage the development of new management pathways and interventions to address the unacceptably high mortality.

ObjectiveHepatocellular carcinoma (HCC) is an infrequent yet critical event in primary biliary cirrhosis (PBC); however, predictive tools remain ill-defined. Our objective was to identify candidate risk factors for HCC development in patients with PBC.DesignRisk factor analysis was performed in over 15 centres from North America and Europe spanning >40 years observation period using Cox proportional hazards assumptions, logistic regression, and Kaplan-Meier estimates.ResultsOf 4565 patients with PBC 123 developed HCC, yielding an incidence rate (IR) of 3.4 cases/1000 patient-years. HCC was significantly more common in men (p<0.0001), and on univariate analysis factors at PBC diagnosis associated with future HCC development were male sex (unadjusted HR 2.91, p<0.0001), elevated serum aspartate transaminase (HR 1.24, p<0.0001), advanced disease (HR 2.72, p=0.022), thrombocytopenia (HR 1.65, p<0.0001), and hepatic decompensation (HR 9.89, p<0.0001). As such, non-treatment with ursodeoxycholic acid itself was not associated with cancer development; however, 12-month stratification by biochemical non-response (Paris-I criteria) associated significantly with future risk of HCC (HR 4.52, p<0.0001; IR 6.6 vs 1.4, p<0.0001). Non-response predicted future risk in patients with early stage disease (IR 4.7 vs 1.2, p=0.005), advanced disease (HR 2.79, p=0.02; IR 11.2 vs 4.4, p=0.033), and when restricting the analysis to only male patients (HR 4.44, p<0.001; IR 18.2 vs 5.4, p<0.001). On multivariable analysis biochemical non-response remained the most significant factor predictive of future HCC risk (adjusted HR 3.44, p<0.0001).ConclusionsThis uniquely powered, internationally representative cohort robustly demonstrates that 12-month biochemical non-response is associated with increased future risk of developing HCC in PBC. Such risk stratification is relevant to patient care and development of new therapies.

Background Although malnutrition and sarcopenia are prevalent in cirrhosis, their impact on outcomes following liver transplantation is not well documented. Methods The associations of nutritional status and sarcopenia with post‐transplant infections, requirement for mechanical ventilation, intensive care (ICU) and hospital stay, and 1 year mortality were assessed in 232 consecutive transplant recipients. Nutritional status and sarcopenia were assessed using the Royal Free Hospital‐Global Assessment (RFH‐GA) tool and the L3‐psoas muscle index (L3‐PMI) on CT, respectively. Results A wide range of RFH‐SGA and L3‐PMI were observed within similar Model for End‐stage Liver Disease (MELD) sub‐categories. Malnutrition and sarcopenia were independent predictors of all outcomes. Post‐transplant infections were associated with MELD (OR = 1.055, 95%CI = 1.002–1.11) and severe malnutrition (OR = 6.55, 95%CI = 1.99–21.5); ventilation > 24 h with MELD (OR = 1.1, 95%CI = 1.036–1.168), severe malnutrition (OR = 8.5, 95%CI = 1.48–48.87) and suboptimal donor liver (OR = 2.326, 95%CI = 1.056–5.12); ICU stay > 5 days, with age (OR = 1.054, 95%CI = 1.004–1.106), MELD (OR = 1.137, 95%CI = 1.057–1.223) and severe malnutrition (OR = 7.46, 95%CI = 1.57–35.43); hospital stay > 20 days with male sex (OR = 2.107, 95%CI = 1.004–4.419) and L3‐PMI (OR = 0.996, 95%CI = 0.994–0.999); 1 year mortality with L3‐PMI (OR = 0.996, 95%CI = 0.992–0.999). Patients at the lowest L3‐PMI receiving suboptimal grafts had longer ICU/hospital stay and higher incidence of infections. Conclusions Malnutrition and sarcopenia are associated with early post‐liver transplant morbidity/mortality. Allocation indices do not include nutritional status and may jeopardize outcomes in nutritionally compromised individuals.

We assessed the prognostic significance of infections in relation to current prognostic scores and explored if infection could be considered per se a distinct clinical stage in the natural history of cirrhosis. We included consecutive patients with cirrhosis admitted to a tertiary referral liver unit for at least 48 h over a 2-year period. Diagnosis of infection was based on positive cultures or strict established criteria. We used competing risk analysis and propensity score matching for data analysis. 501 patients (63% male, 48% alcoholic liver disease, median Model of End-stage Liver Disease (MELD)=17) underwent 781 admissions over the study period. Portal hypertensive bleeding and complicated ascites were the commonest reasons of admission. The incidence of proven bacterial infection was 25.6% (60% community acquired and 40% nosocomial). Survival rates at 3, 6, 12, and 30 months were 83%, 77%, 71%, and 62% in patients without diagnosis of infection, vs. 50%, 46%, 41%, and 34% in patients with diagnosis of infection. Overall survival was independently associated with MELD score (hazards ratio (HR) 1.099), intensive care (ITU) stay (HR 1.967) and bacterial infection (HR 2.226). Bacterial infection was an independent predictor of survival even when patients who died within the first 30 days were excluded from the analysis in Cox regression (HR 2.013) and competing risk Cox models in all patients (HR 1.46) and propensity risk score-matched infected and non-infected patients (HR 1.67). Infection most likely represents a distinct prognostic stage of cirrhosis, which affects survival irrespective of disease severity, even after recovery from the infective episode.

BackgroundTransjugular intrahepatic portosystemic shunt (TIPS) has proven clinical efficacy as rescue therapy for cirrhotic patients with acute portal hypertensive bleeding who fail endoscopic treatment.AimsTo investigate predictive factors of 6-week and 1-year mortality in patients undergoing salvage TIPS for refractory portal hypertensive bleeding.MethodsA total of 144 consecutive patients were retrospectively evaluated. Three logistic regression multivariate models were estimated to individualize prognostic factors for 6-week and 12-month mortality. Log-rank test was used to evaluate survival according to Child–Pugh classes and Bureau’s criteria.ResultsMean age 51 ± 10 years, 66% male, mean MELD 18.5 ± 8.3, Child–Pugh A/B/C 8%/38%/54%. TIPS failure occurred in 23(16%) patients and was associated with pre-TIPS portal pressure gradient and pre-TIPS intensive care unit stay. Six-week and 12-month mortality was 36% and 42%, respectively. Pre-TIPS intensive care unit stay, MELD, and Child–Pugh score were independently associated with mortality at 6 weeks. Independent predictors of mortality at 12 months were pre-TIPS intensive care unit stay and Child–Pugh score.ConclusionsIn this large cohort of patients undergoing salvage TIPS, MELD and Child–Pugh scores were predictive of short- and long-term mortality, respectively. Pre-TIPS intensive care unit stay was independently associated with TIPS failure and mortality at 6 weeks and 12 months. Salvage TIPS is futile in patients with Child–Pugh score of 14–15.

Cytomegalovirus end-organ disease can be prevented by giving ganciclovir when viraemia is detected in allograft recipients. Values of viral load correlate with development of end-organ disease and are moderated by pre-existing natural immunity. Our aim was to determine whether vaccine-induced immunity could do likewise. We undertook a phase-2 randomised placebo controlled trial in adults awaiting kidney or liver transplantation at the Royal Free Hospital, London, UK. Exclusion criteria were pregnancy, receipt of blood products (except albumin) in the previous 3 months, and simultaneous multiorgan transplantation. 70 patients seronegative and 70 seropositive for cytomegalovirus were randomly assigned from a scratch-off randomisation code in a 1:1 ratio to receive either cytomegalovirus glycoprotein-B vaccine with MF59 adjuvant or placebo, each given at baseline, 1 month and 6 months later. If a patient was transplanted, no further vaccinations were given and serial blood samples were tested for cytomegalovirus DNA by real-time quantitative PCR (rtqPCR). Any patient with one blood sample containing more than 3000 cytomegalovirus genomes per mL received ganciclovir until two consecutive undetectable cytomegalovirus DNA measurements. Safety and immunogenicity were coprimary endpoints and were assessed by intention to treat in patients who received at least one dose of vaccine or placebo. This trial is registered with ClinicalTrials.gov, NCT00299260. 67 patients received vaccine and 73 placebo, all of whom were evaluable. Glycoprotein-B antibody titres were significantly increased in both seronegative (geometric mean titre 12 537 (95% CI 6593–23 840) versus 86 (63–118) in recipients of placebo recipients; p<0·0001) and seropositive (118 395; 64 503–217 272) versus 24 682 (17 909–34 017); p<0·0001) recipients of vaccine. In those who developed viraemia after transplantation, glycoprotein-B antibody titres correlated inversely with duration of viraemia (p=0·0022). In the seronegative patients with seropositive donors, the duration of viraemia (p=0·0480) and number of days of ganciclovir treatment (p=0·0287) were reduced in vaccine recipients. Although cytomegalovirus disease occurs in the context of suppressed cell-mediated immunity post-transplantation, humoral immunity has a role in reduction of cytomegalovirus viraemia. Vaccines containing cytomegalovirus glycoprotein B merit further assessment in transplant recipients. National Institute of Allergy and Infectious Diseases, Grant R01AI051355 and Wellcome Trust, Grant 078332. Sponsor: University College London (UCL).

[...]cirrhosis is also a major indication for the transfusion of blood components to treat bleeding and also for prophylaxis of bleeding. 11 The most devastating haemorrhagic complication remains variceal haemorrhage. [...]survival was increased with anticoagulation. 52 Although these are important data for proof of concept, larger, multicentre pragmatic trials with sufficient power and longitudinal follow-up will be required to examine the potential role of anticoagulation either as a therapeutic modality to reduce progression of fibrosis or for prevention of decompensation in those with early cirrhosis.

Chemoembolization (TACE) improves survival in cirrhotic patients with hepatocellular carcinoma (HCC). The optimal schedule, or whether embolization (TAE) alone gives the same survival advantage, is not known. To evaluate whether specific patient characteristics and/or radiological transarterial techniques result in better outcomes. A PubMed search was carried out for cohort and randomized trials (n = 175) testing transarterial therapies; meta-analysis was performed where appropriate. Anticancer drugs were used as sole agent in 75% of cases (double 15% and triple 6%): doxorubicin (36%), cisplatin (31%), epirubicin (12%), mitoxantrone (8%), mitomycin (8%), and SMANCS (5%). Embolizing agents used were: gelatin sponge particles (71%), polyvinyl alcohol (PVA) particles (8%), degradable starch microspheres (DSM) (4%), and embospheres (4%). Sessions per patient were 2.5 +/- 1.5 (interval: 2 months). Objective response was 40 +/- 20%; survival rates at 1, 2, 3, and 5 years were: 62 +/- 20%, 42 +/- 17%, 30 +/- 15%, and 19 +/- 16%, respectively, and survival time was 18 +/- 9.5 months. The post-TACE complications were: acute liver failure, 7.5% (range 0-49%); acute renal failure, 1.8% (0-13%); encephalopathy, 1.8% (0-16%); ascites, 8.3% (0-52%); upper gastrointestinal bleeding; 3% (0-22%); and hepatic or splenic abscess, 1.3% (0-2.5%). Treatment-related mortality was 2.4% (0-9.5%), mainly due to acute liver failure. Our meta-analysis of nine randomized controlled trials (RCTs) confirmed that TACE improves survival; but a meta-analysis of TACE versus TAE alone (3 RCTs, 412 patients) demonstrated no survival difference. No chemotherapeutic agent appears better than any other. There is no evidence for benefit with lipiodol. Gelatin sponge is the most used embolic agent, but PVA particles may be better. TAE appears as effective as TACE. New strategies to reduce the risk of post-TACE complications are required.

Selected patients with hepatocellular carcinoma are candidates to receive potentially curative treatments, such as hepatic resection or liver transplantation, but nevertheless there is a high risk of tumor recurrence. Microvascular invasion is a histological feature of hepatocellular carcinoma related to aggressive biological behavior. We systematically reviewed 20 observational studies that addressed the prognostic impact of microvascular invasion, either after liver transplantation or resection. Outcomes were disease-free survival and overall survival. In liver transplantation, the presence of microvascular invasion shortened disease-free survival at 3 years (relative risk (RR) = 3.41 [2.05–5.7]; five studies, n  = 651) and overall survival both at 3 years (RR = 2.41 [1.72–3.37]; five studies, n  = 1,938) and 5 years (RR = 2.29 [1.85–2.83]; six studies, n  = 2,003). After liver resection, microvascular invasion impacted disease-free survival at 3 and 5 years (RR = 1.82 [1.61–2.07] and RR = 1.51 [1.29–1.77]; four studies, n  = 1,501 for both comparisons). However inter/intraobserver variability in reporting and the lack of definition and grading of microvascular invasion has led to great heterogeneity in evaluating this histological feature in hepatocellular carcinoma. Thus, there is an urgent need to clarify this issue, because determining prognosis and response to therapy have become important in the current management of hepatocellular carcinoma. In this systematic review, we summarize the diagnostic and prognostic data concerning microvascular invasion in hepatocellular carcinoma and present a basis for consensus on its definition.