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Albumin is the most abundant protein in the human body and is synthetized exclusively by the liver. Therefore, serum albumin levels are reduced in acute and/or chronic liver disease. In cirrhosis, low levels of albumin predict the outcome. In advanced cirrhosis, the quality of albumin is decreased due to high oxidative stress and a proinflammatory state. Therefore, the administration of i.v. albumin would seem to be of pathophysiological relevance and benefit. Yet, the questions that remain are who, when, how much, and how often. While albumin infusion is recommended after large-volume paracentesis, at diagnosis of spontaneous bacterial peritonitis, in acute kidney injury, and in hepatorenal syndrome, the amount and schedule of albumin to be administered require refinement, particularly given complications related to volume overload that have become increasingly apparent. Other indications for albumin such as infections other than spontaneous bacterial peritonitis, hyponatremia, HE, prevention of poor outcomes in hospitalized, and in outpatients with cirrhosis are still debated. The results of studies in these settings are either negative, controversial, or inconclusive. This sheds some doubts regarding the use of albumin as a "one size fits all" strategy. The indication and patient selection are crucial and not always intuitive. The amount and frequency also seem to play a role in the success or failure of albumin. This review will critically discuss the evidence and underline areas where there are indications for albumin use and others where evidence is still insufficient and will have to await the development/results of randomized controlled trials., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Aims: Alcohol-associated hepatitis (AH) is associated with very high mortality despite abstinence from alcohol; up to 40% of patients die within 6 months of diagnosis. Patients with AH are especially prone to infections, which can lead to multiorgan dysfunction and poorer prognosis., Approach and Results: We performed comprehensive serological profiling of the viral and bacterial infection history of 36 healthy controls, 48 patients with alcohol use disorder, and 224 patients with AH from 2 multicenter observational studies. We used systematic viral and bacterial epitope scanning by VirScan, a phage-display immunoprecipitation and sequencing technology that detects the peptides recognized by antibodies in patient sera, to comprehensively analyze antiviral and antibacterial antibodies and identify serologic biomarkers to predict patient outcomes. We found significant differences in the serological profiles of the 3 populations. The number of serum antibody epitopes in patients with alcohol use disorder during abstinence was increased compared with during active alcohol use. A decreased number and diversity of viral and bacterial antibody targets were detected in the sera of patients with AH, particularly those with a higher Child-Pugh score. In patients with AH, a decrease in the serum antiviral, but not antibacterial, antibody repertoire was associated with decompensation and mortality. Ninety-day mortality in AH could be predicted using a serum viral epitope signature., Conclusions: Abstinence from alcohol is associated with a significant increase in serum viral and bacterial antibody response. Decreased serum antiviral antibody repertoire is predictive of decompensation of liver disease and mortality in patients with AH., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background and Aims: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH., Approach and Results: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group., Conclusions: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background and Aims: The prognostic weight of further decompensation in cirrhosis is still unclear. We investigated the incidence of further decompensation and its effect on mortality in patients with cirrhosis., Approach and Results: Multicenter cohort study. The cumulative incidence of further decompensation (development of a second event or complication of a decompensating event) was assessed using competing risks analysis in 2028 patients. A 4-state model was built: first decompensation, further decompensation, liver transplant, and death. A cause-specific Cox model was used to assess the adjusted effect of further decompensation on mortality. Sensitivity analyses were performed for patients included before or after 1999. In a mean follow-up of 43 months, 1192 patients developed further decompensation and 649 died. Corresponding 5-year cumulative incidences were 52% and 35%, respectively. The cumulative incidences of death and liver transplant after further decompensation were 55% and 9.7%, respectively. The most common further decompensating event was ascites/complications of ascites. Five-year probabilities of state occupation were 24% alive with first decompensation, 21% alive with further decompensation, 7% alive with a liver transplant, 16% dead after first decompensation without further decompensation, 31% dead after further decompensation, and <1% dead after liver transplant. The HR for death after further decompensation, adjusted for known prognostic indicators, was 1.46 (95% CI: 1.23-1.71) ( p <0.001). The significant impact of further decompensation on survival was confirmed in patients included before or after 1999., Conclusions: In cirrhosis, further decompensation occurs in ~60% of patients, significantly increases mortality, and should be considered a more advanced stage of decompensated cirrhosis., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background and Aims: Acute kidney injury (AKI) has a poor prognosis in cirrhosis. Given the variability of creatinine, the prediction of AKI and dialysis by other markers is needed. The aim of this study is to determine the role of serum and urine metabolomics in the prediction of AKI and dialysis in an inpatient cirrhosis cohort., Approach and Results: Inpatients with cirrhosis from 11 North American Consortium of End-stage Liver Disease centers who provided admission serum/urine when they were AKI and dialysis-free were included. Analysis of covariance adjusted for demographics, infection, and cirrhosis severity was performed to identify metabolites that differed among patients (1) who developed AKI or not; (2) required dialysis or not; and/pr (3) within AKI subgroups who needed dialysis or not. We performed random forest and AUC analyses to identify specific metabolite(s) associated with outcomes. Logistic regression with clinical variables with/without metabolites was performed. A total of 602 patients gave serum (218 developed AKI, 80 needed dialysis) and 435 gave urine (164 developed AKI, 61 needed dialysis). For AKI prediction, clinical factor-adjusted AUC was 0.91 for serum and 0.88 for urine. Major metabolites such as uremic toxins (2,3-dihydroxy-5-methylthio-4-pentenoic acid [DMTPA], N2N2dimethylguanosine, uridine/pseudouridine) and tryptophan/tyrosine metabolites (kynunerate, 8-methoxykyunerate, quinolinate) were higher in patients who developed AKI. For dialysis prediction, clinical factor-adjusted AUC was 0.93 for serum and 0.91 for urine. Similar metabolites as AKI were altered here. For dialysis prediction in those with AKI, the AUC was 0.81 and 0.79 for serum/urine. Lower branched-chain amino-acid (BCAA) metabolites but higher cysteine, tryptophan, glutamate, and DMTPA were seen in patients with AKI needing dialysis. Serum/urine metabolites were additive to clinical variables for all outcomes., Conclusions: Specific admission urinary and serum metabolites were significantly additive to clinical variables to predict AKI development and dialysis initiation in inpatients with cirrhosis. These observations can potentially facilitate earlier initiation of renoprotective measures., (© 2021 by the American Association for the Study of Liver Diseases.)

Background and Aims: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD., Approach and Results: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality., Conclusions: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH., (© 2020 by the American Association for the Study of Liver Diseases.)

The severe acute respiratory syndrome coronavirus 2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C and studying the natural history of many forms of chronic liver disease. National Institutes of Health, foundation, and industry funding have provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all nonessential research activities were halted when the pandemic started, forcing those involved in clinical research to rethink their research strategy, including a shift to coronavirus disease 2019 research while endeavoring to maintain their preexisting agenda. Strategies to maintain the integrity of ongoing studies, including patient follow-up, safety assessments, and continuation of investigational products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a revamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the predetermined time frame, and the need to reprogram career path timelines. Real-world databases, biomarker and long-term follow up studies, and research involving special groups (children, the homeless, and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Recent evidence suggests that acute kidney injury (AKI) is the main predictor of postparacentesis bleeding in patients with cirrhosis. To assess the factors responsible for bleeding tendency in AKI, we performed a prospective study comparing all three aspects of hemostasis (platelets, coagulation, and fibrinolysis) in patients with decompensated cirrhosis with and without AKI., Approach and Results: Primary hemostasis assessment included platelet aggregation and secretion (platelet function markers) and von Willebrand factor. Secondary hemostasis assessment included pro-coagulant (factor VIII and factor XIII) and anti-coagulant (protein C, protein S, and antithrombin) factors and thrombin generation. Tertiary hemostasis assessment included fibrinolytic factors and plasmin-antiplasmin complex. Eighty patients with decompensated cirrhosis were recruited (40 each with and without AKI). Severity of cirrhosis and platelet count were comparable between groups. Median serum creatinine was 1.8 mg/dL and 0.8 mg/dL in patients with and without AKI, respectively. At baseline, patients with cirrhosis and AKI had lower platelet aggregation and secretion, indicative of impaired platelet function (increased bleeding tendency), without differences in von Willebrand factor. Regarding coagulation factors, factor VIII was higher, whereas protein C, protein S, and antithrombin were all lower, which, together with increased thrombin generation, indicate hypercoagulability. In contrast, factor XIII was lower in AKI (increased bleeding tendency). Finally, while both hypofibrinolytic and hyperfibrinolytic changes were present in AKI, a higher plasmin-antiplasmin complex indicated a hyperfibrinolytic state. After AKI resolution (n = 23 of 40), platelet function and coagulation improved to levels observed in patients with cirrhosis patients without AKI; however, fibrinolysis remained hyperactivated., Conclusions: In patients with decompensated cirrhosis, AKI is associated with both hypocoagulable and hypercoagulable features that can potentially increase the risk of both bleeding and thrombosis., (© 2020 by the American Association for the Study of Liver Diseases.)

Background and Aims: Prevention of decompensation is a primary therapeutic target in patients with compensated cirrhosis (CC). However, a major problem is the large sample size and long follow-up required to demonstrate a significant treatment effect because of the relatively low baseline risk. For this reason, it has been recently suggested that ordinal outcomes may be used in this area to gain power and reduce sample size. The aim of this study was to assess the applicability of ordinal outcomes in cirrhosis., Approach and Results: An inception cohort of 202 patients with CC (no ascites, gastrointestinal bleeding, encephalopathy, or jaundice) without esophageal varices was included, and 5-year outcome is reported. Etiology was mostly viral and alcoholic, and there were no dropouts. Ordinal outcome was set according to six grades with a previously established prognostic ordinality: grade 1 = no disease progression; grade 2 = development of varices; grade 3 = bleeding alone; grade 4 = nonbleeding single decompensation; grade 5 = more than one decompensating event; and grade 6 = death. At the 60-month time point, patients were distributed in grades 1 through 6 as follows: 129, 43, 2, 7, 5, and 16, respectively. Emulation of a clinical trial performed by dividing patients based on baseline platelet count into two groups (cutoff, 150 × 10 9 /L) demonstrated a statistically significant outcome difference between groups when using ordinal outcomes not detectable by binary logistic or chi-square or time-to-event analyses. Additionally, using ordinal outcomes in a hypothetical study to prevent decompensation resulted in sample-size estimates 3-to 4-fold lower than using a binary composite endpoint., Conclusions: Compared to traditional binary outcomes, the use of ordinal outcomes in trials of cirrhosis decompensation may provide more power and thus may require a smaller sample size., (© 2020 by the American Association for the Study of Liver Diseases.)

Chronic alcohol consumption causes increased intestinal permeability and changes in the intestinal microbiota composition, which contribute to the development and progression of alcohol-related liver disease. In this setting, little is known about commensal fungi in the gut. We studied the intestinal mycobiota in a cohort of patients with alcoholic hepatitis, patients with alcohol use disorder, and nonalcoholic controls using fungal-specific internal transcribed spacer amplicon sequencing of fecal samples. We further measured serum anti-Saccharomyces cerevisiae antibodies (ASCA) as a systemic immune response to fungal products or fungi. Candida was the most abundant genus in the fecal mycobiota of the two alcohol groups, whereas genus Penicillium dominated the mycobiome of nonalcoholic controls. We observed a lower diversity in the alcohol groups compared with controls. Antibiotic or steroid treatment was not associated with a lower diversity. Patients with alcoholic hepatitis had significantly higher ASCA levels compared to patients with alcohol use disorder and to nonalcoholic controls. Within the alcoholic hepatitis cohort, patients with levels of at least 34 IU/mL had a significantly lower 90-day survival (59%) compared with those with ASCA levels less than 34 IU/mL (80%) with an adjusted hazard ratio of 3.13 (95% CI, 1.11-8.82; P = 0.031). Conclusion: Patients with alcohol-associated liver disease have a lower fungal diversity with an overgrowth of Candida compared with controls. Higher serum ASCA was associated with increased mortality in patients with alcoholic hepatitis. Intestinal fungi may serve as a therapeutic target to improve survival, and ASCA may be useful to predict the outcome in patients with alcoholic hepatitis., (© 2019 by the American Association for the Study of Liver Diseases.)

Portal hypertension (PH) is the main driver of cirrhosis decompensation, the main determinant of death in patients with cirrhosis. PH results initially from increased intrahepatic vascular resistance. Subsequently, increased inflow from splanchnic vasodilation and increased cardiac output lead to a further increase in portal pressure (PP). Reducing PP in cirrhosis results in better outcomes. Removing the cause of cirrhosis might improve PP. However, this is a slow process and patients may continue to be at risk of decompensation. Additionally, for some chronic liver diseases, such as nonalcoholic fatty liver disease (NAFLD), etiological treatments are not yet available. Therefore, there is a need to develop better therapies specifically aimed at reducing PP. For over 35 years, the mainstay of such therapy has been the use of nonselective beta-blockers (NSBBs) that act by reducing portal venous inflow. Recently, many drugs (mainly targeting intrahepatic mechanisms) have shown promise in preclinical and early clinical studies and may act alone or synergistically with NSBBs in reducing PP in cirrhosis. The objective of this position paper is to propose a novel framework for the design of clinical trials (phase 1, 2, and 3) in patients with cirrhosis and PH and to prioritize targets and pharmacological therapies in this setting. We have focused the discussion on patients with compensated cirrhosis. The paper summarizes discussions held at The American Association for the Study of Liver Diseases (AASLD) Industry Colloquium in January 2018, with the participation of clinical and translational investigators, regulatory professionals, and industry partners., (© 2018 by the American Association for the Study of Liver Diseases.)

Caspases play a central role in apoptosis, inflammation, and fibrosis. They produce hemodynamically active, proinflammatory microparticles that cause intrahepatic inflammation, vasoconstriction, and extrahepatic splanchnic vasodilation. Emricasan is a pan-caspase inhibitor that lowers portal hypertension (PH) and improves survival in murine models of cirrhosis. This exploratory study assessed whether emricasan lowers PH in patients with compensated cirrhosis. This multicenter, open-label study enrolled 23 subjects with compensated cirrhosis and PH (hepatic vein pressure gradient [HVPG] >5 mm Hg). Emricasan 25 mg twice daily was given for 28 days. HVPG measurements were standardized and performed before and after emricasan. A single expert read all HVPG tracings. Median age was 59 (range 49-80); 70% were male. Cirrhosis etiologies were nonalcoholic steatohepatitis and hepatitis C virus. Subjects were Child class A (87%) with a median Model for End-Stage Liver Disease score of 8 (range 6-15). Twelve had severe PH (HVPG ≥12 mm Hg). Overall, there was no significant change in HVPG after emricasan (mean [standard deviation, SD] -1.1 [4.57] mm Hg). HVPG decreased significantly (mean [SD] -3.7[4.05] mm Hg; P = 0.003) in those with severe PH: 4/12 had a ≥20% decrease, 8/12 had a ≥10% decrease, and 2/12 HVPG decreased below 12 mm Hg. There were no significant changes in blood pressure or heart rate. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) decreased significantly in the entire group and in those with severe PH. Serum cleaved cytokeratin 18 and caspase-3/7 decreased significantly. Emricasan was well tolerated. One subject discontinued for nonserious adverse events. Conclusion: Emricasan administered for 28 days decreased HVPG in patients with compensated cirrhosis and severe PH; an effect upon portal venous inflow is likely, and concomitant decreases in AST/ALT suggest an intrahepatic anti-inflammatory effect., (© 2018 The Authors. Hepatology published by Wiley Periodicals, Inc. on behalf of American Association for the Study of Liver Diseases.)

The North American Consortium for the Study of End-Stage Liver Disease's definition of acute-on-chronic liver failure (NACSELD-ACLF) as two or more extrahepatic organ failures has been proposed as a simple bedside tool to assess the risk of mortality in hospitalized patients with cirrhosis. We validated the NACSELD-ACLF's ability to predict 30-day survival (defined as in-hospital death or hospice discharge) in a separate multicenter prospectively enrolled cohort of both infected and uninfected hospitalized patients with cirrhosis. We used the NACSELD database of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 2,675). The cohort was randomly split 60%/40% into training (n = 1,605) and testing (n = 1,070) groups. Organ failures assessed were (1) shock, (2) hepatic encephalopathy (grade III/IV), (3) renal (need for dialysis), and (4) respiratory (mechanical ventilation). Patients were most commonly Caucasian (79%) men (62%) with a mean age of 57 years and a diagnosis of alcohol-induced cirrhosis (45%), and 1,079 patients had an infection during hospitalization. The mean Model for End-Stage Liver Disease score was 19, and the median Child score was 10. No demographic differences were present between the two split groups. Multivariable modeling revealed that the NACSELD-ACLF score, as determined by number of organ failures, was the strongest predictor of decreased survival after controlling for admission age, white blood cell count, serum albumin, Model for End-Stage Liver Disease score, and presence of infection. The c-statistics were 0.8073 for the training set and 0.8532 for the validation set., Conclusion: Although infection status remains an important predictor of death, NACSELD-ACLF was independently validated in a separate large multinational prospective cohort as a simple, reliable bedside tool to predict 30-day survival in both infected and uninfected patients hospitalized with a diagnosis of cirrhosis. (Hepatology 2018;67:2367-2374)., (© 2018 by the American Association for the Study of Liver Diseases.)

Endoscopic variceal ligation plus beta-blockers (EVL+BB) is currently recommended for variceal rebleeding prophylaxis, a recommendation that extends to all patients with cirrhosis with previous variceal bleeding irrespective of prognostic stage. Individualizing patient care is relevant, and in published studies on variceal rebleeding prophylaxis, there is a lack of information regarding response to therapy by prognostic stage. This study aimed at comparing EVL plus BB with monotherapy (EVL or BB) on all-source rebleeding and mortality in patients with cirrhosis and previous variceal bleeding stratified by cirrhosis severity (Child A versus B/C) by means of individual time-to-event patient data meta-analysis from randomized controlled trials. The study used individual data on 389 patients from three trials comparing EVL plus BB versus BB and 416 patients from four trials comparing EVL plus BB versus EVL. Compared with BB alone, EVL plus BB reduced overall rebleeding in Child A (incidence rate ratio 0.40; 95% confidence interval, 0.18-0.89; P = 0.025) but not in Child B/C, without differences in mortality. The effect of EVL on rebleeding was different according to Child (P for interaction <0.001). Conversely, compared with EVL, EVL plus BB reduced rebleeding in both Child A and B/C, with a significant reduction in mortality in Child B/C (incidence rate ratio 0.46; 95% confidence interval, 0.25-0.85; P = 0.013)., Conclusion: Outcomes of therapies to prevent variceal rebleeding differ depending on cirrhosis severity: in patients with preserved liver function (Child A), combination therapy is recommended because it is more effective in preventing rebleeding, without modifying survival, while in patients with advanced liver failure (Child B/C), EVL alone carries an increased risk of rebleeding and death compared with combination therapy, underlining that BB is the key element of combination therapy. (Hepatology 2017;66:1219-1231)., (© 2017 by the American Association for the Study of Liver Diseases.)

Identification of patients with cirrhosis at risk for death within 3 months of discharge from the hospital is essential to individualize postdischarge plans. The objective of the study was to identify an easy-to-use prognostic model based on the Karnofsky Performance Status (KPS). The North American Consortium for the Study of End-Stage Liver Disease consists of 16 tertiary-care hepatology centers that prospectively enroll nonelectively admitted cirrhosis patients. Patients enrolled had KPS assessed 1 week postdischarge. KPS was categorized into low (score 10-40), intermediate (50-70), and high (80-100). Of 954 middle-aged patients (57 ± 10 years, 63% men) with a median Model for End-Stage Liver Disease (MELD) score of 17 (interquartile range 13-21), the mortality rates for the low, intermediate, and high performance status groups were 23% (36/159), 11% (55/489), and 5% (15/306), respectively. Low, intermediate, and high performance status was seen in 17%, 51%, and 32% of the cohort, respectively. Low performance status was associated with older age, dialysis, hepatic encephalopathy, longer length of stay, and higher white blood cell count or MELD score at discharge. A model was derived using the three independent predictors of 3-month mortality: KPS, age, and MELD score. This score had better discrimination (area under the receiver operating characteristic curve = 0.74) than a model using MELD (area under the receiver operating characteristic curve = 0.62) or MELD and age (area under the receiver operating characteristic curve = 0.67) to predict 3-month mortality., Conclusions: Cirrhosis patients at risk for 3-month postdischarge mortality can be identified using a novel KPS-based score; this score may be adopted in practice to guide postdischarge early interventions, including the integrated provision of active and palliative management strategies. (Hepatology 2017;65:217-224)., (© 2016 by the American Association for the Study of Liver Diseases.)

Competing Interests: No conflict of interest

Unlabelled: In smaller single-center studies, patients with cirrhosis are at a high readmission risk, but a multicenter perspective study is lacking. We evaluated the determinants of 3-month readmissions among inpatients with cirrhosis using the prospective 14-center North American Consortium for the Study of End-Stage Liver Disease cohort. Patients with cirrhosis hospitalized for nonelective indications provided consent and were followed for 3 months postdischarge. The number of 3-month readmissions and their determinants on index admission and discharge were calculated. We used multivariable logistic regression for all readmissions and for hepatic encephalopathy (HE), renal/metabolic, and infection-related readmissions. A score was developed using admission/discharge variables for the total sample, which was validated on a random half of the total population. Of the 1353 patients enrolled, 1177 were eligible on discharge and 1013 had 3-month outcomes. Readmissions occurred in 53% (n = 535; 316 with one, 219 with two or more), with consistent rates across sites. The leading causes were liver-related (n = 333; HE, renal/metabolic, and infections). Patients with cirrhosis and with worse Model for End-Stage Liver Disease score or diabetes, those taking prophylactic antibiotics, and those with prior HE were more likely to be readmitted. The admission model included Model for End-Stage Liver Disease and diabetes (c-statistic = 0.64, after split-validation 0.65). The discharge model included Model for End-Stage Liver Disease, proton pump inhibitor use, and lower length of stay (c-statistic = 0.65, after split-validation 0.70). Thirty percent of readmissions could not be predicted. Patients with liver-related readmissions consistently had index-stay nosocomial infections as a predictor for HE, renal/metabolic, and infection-associated readmissions (odds ratio = 1.9-3.0)., Conclusions: Three-month readmissions occurred in about half of discharged patients with cirrhosis, which were associated with cirrhosis severity, diabetes, and nosocomial infections; close monitoring of patients with advanced cirrhosis and prevention of nosocomial infections could reduce this burden. (Hepatology 2016;64:200-208)., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: Patients with cirrhosis, particularly those with decompensated cirrhosis, are at increased risk of bacterial infections that may further precipitate other liver decompensations including acute-on-chronic liver failure. Infections constitute the main cause of death in patients with advanced cirrhosis, and strategies to prevent them are essential. The main current strategy is the use of prophylactic antibiotics targeted at specific subpopulations at high risk of infection: prior episode of spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and low-protein ascites with associated poor liver function. Antibiotic prophylaxis effectively prevents not only the development of bacterial infections in all these indications but also further decompensation (variceal bleeding, hepatorenal syndrome) and improves survival. However, antibiotic prophylaxis is also associated with a clinically relevant and increasing drawback, the development of infections due to multidrug-resistant organisms. Several strategies have been suggested to balance the risks and benefits of antibiotic prophylaxis., Conclusion: Antibiotic stewardship principles such as the restriction of antibiotic prophylaxis to subpopulations at a very high risk for infection, the avoidance of antibiotic overuse, and early deescalation policies are key to achieve this balance; nonantibiotic prophylactic measures such as probiotics, prokinetics, bile acids, statins, and hematopoietic growth factors could also contribute to ameliorate the development and spread of multidrug-resistant bacteria in cirrhosis. (Hepatology 2016;63:2019-2031)., (© 2015 by the American Association for the Study of Liver Diseases. This article has been contributed to by U.S. government employees, and their contribution is in the public domain in the U.S.A.)

Unlabelled: Bleeding is a feared complication of invasive procedures in patients with cirrhosis and significant coagulopathy (as defined by routine coagulation tests) and is used to justify preprocedure use of fresh frozen plasma (FFP) and/or platelets (PLT). Thromboelastography (TEG) provides a more comprehensive global coagulation assessment than routine tests (international normalized ratio [INR] and platelet count), and its use may avoid unnecessary blood product transfusion in patients with cirrhosis and significant coagulopathy (defined in this study as INR >1.8 and/or platelet count <50 × 10(9) /L) who will be undergoing an invasive procedure. Sixty patients were randomly allocated to TEG-guided transfusion strategy or standard of care (SOC; 1:1 TEG:SOC). The TEG group would receive FFP if the reaction time (r) was >40 min and/or PLT if maximum amplitude (MA) was <30 mm. All SOC patients received FFP and/or PLT per hospital guidelines. Endpoints were blood product use and bleeding complications. Baseline characteristics of the two groups were similar. Per protocol, all subjects in the SOC group received blood product transfusions versus 5 in the TEG group (100% vs. 16.7%; P < 0.0001). Sixteen SOC (53.3%) received FFP, 10 (33.3%) PLT, and 4 (13.3%) both FFP and PLT. In the TEG group, none received FFP alone (P < 0.0001 vs. SOC), 2 received PLT (6.7%; P = 0.009 vs. SOC), and 3 both FFP and PLT (not significant). Postprocedure bleeding occurred in only 1 patient (SOC group) after large-volume paracentesis., Conclusions: In patients with cirrhosis and significant coagulopathy before invasive procedures, TEG-guided transfusion strategy leads to a significantly lower use of blood products compared to SOC (transfusion guided by INR and platelet count), without an increase in bleeding complications. Remarkably, even in patients with significant coagulopathy, postprocedure bleeding was rare, indicating that TEG thresholds should be reevaluated., (© 2015 by the American Association for the Study of Liver Diseases.)

Unlabelled: Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia (PRA), acute tubular necrosis (ATN), and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical, as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step-wise with the number of biomarkers above optimal diagnostic cutoffs., Conclusion: Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: Infections worsen survival in cirrhosis; however, simple predictors of survival in infection-related acute-on-chronic liver failure (I-ACLF) derived from multicenter studies are required in order to improve prognostication and resource allocation. Using the North American Consortium for Study of End-stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus [HCV], 15.8% nosocomial infection, 96% Child score ≥ 7) and 30-day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30-day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I-ACLF was defined as ≥ 2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non-SBP infections. Independent predictors of poor 30-day survival were I-ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin., Conclusion: Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I-ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: The rationale for screening inflammatory serum biomarkers of the hepatic vein pressure gradient (HVPG) is based on the fact that portal hypertension is pathogenically related to liver injury and fibrosis, and that in turn these are associated with the activation of inflammatory pathways. This was a nested cohort study in the setting of a randomized, clinical trial to assess the development of gastroesophageal varices (GEV) (N Engl J Med 2005;353:2254). Patients had cirrhosis and portal hypertension but did not have GEV. A total of 90 patients who had baseline day-1 sera available were enrolled in the present study. The objective of this study was to determine whether inflammatory biomarkers in conjunction with clinical parameters could be used to develop a predictive paradigm for HVPG. The correlations between HVPG and interleukin (IL)-1β (P=0.0052); IL-1R-α (P=0.0085); Fas-R (P=0.0354), and serum VCAM-1 (P=0.0007) were highly significant. By using multivariate logistic regression analysis and selected parameters (transforming growth factor beta [TGFβ]; heat shock protein [HSP]-70; at-risk alcohol use; and Child class B) we could exclude HVPG ≥ 12 mmHg with 86% accuracy (95% confidence interval [CI]: 67.78 to 96.16%) and the sensitivity was 87.01% (95% CI: 69.68 to 96.34%). Therefore, the composite test could identify 86% of compensated cirrhosis patients with HVPG below 12 mmHg and prevent unnecessary esophagogastroduodenoscopy with its associated morbidity and costs in these patients. Our diagnostic test was not efficient in predicting HVPG ≥ 12 mmHg., Conclusion: A blood test for HVPG could be performed in cirrhosis patients to prevent unnecessary esophagogastroduodenoscopy., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: Heart failure (HF) is, after cirrhosis, the second-most common cause of ascites. Serum B-type natriuretic peptide (BNP) plays an important role in the diagnosis of HF. Therefore, we hypothesized that BNP would be useful in the differential diagnosis of ascites. Consecutive patients with new onset ascites were prospectively enrolled in this cross-sectional study. All patients had measurements of serum-ascites albumin gradient (SAAG), total protein concentration in ascitic fluid, serum, and ascites BNP. We enrolled 218 consecutive patients with ascites resulting from HF (n = 44), cirrhosis (n = 162), peritoneal disease (n = 10), and constrictive pericarditis (n = 2). Compared to SAAG and/or total protein concentration in ascites, the test that best discriminated HF-related ascites from other causes of ascites was serum BNP. A cutoff of >364 pg/mL (sensitivity 98%, specificity 99%, and diagnostic accuracy 99%) had the highest positive likelihood ratio (168.1); that is, it was the best to rule in HF-related ascites. Conversely, a cutoff ≤ 182 pg/mL had the lowest negative likelihood ratio (0.0) and was the best to rule out HF-related ascites. These findings were confirmed in a 60-patient validation cohort., Conclusions: Serum BNP is more accurate than ascites analyses in the diagnosis of HF-related ascites. The workup of patients with new onset ascites could be streamlined by obtaining serum BNP as an initial test and could forego the need for diagnostic paracentesis, particularly in cases where the cause of ascites is uncertain and/or could be the result of HF., (© 2014 by the American Association for the Study of Liver Diseases.)

Unlabelled: Acute kidney injury (AKI) is a common and devastating complication in patients with cirrhosis. However, the definitions of AKI employed in studies involving patients with cirrhosis have not been standardized, lack sensitivity, and are often limited to narrow clinical settings. We conducted a multicenter, prospective observational cohort study of patients with cirrhosis and AKI, drawn from multiple hospital wards, utilizing the modern acute kidney injury network (AKIN) definition and assessed the association between AKI severity and progression with in-hospital mortality. Of the 192 patients who were enrolled and included in the study, 85 (44%) progressed to a higher AKIN stage after initially fulfilling AKI criteria. Patients achieved a peak severity of AKIN stage 1, 26%, stage 2, 24%, and stage 3, 49%. The incidence of mortality, general medical events (bacteremia, pneumonia, urinary tract infection), and cirrhosis-specific complications (ascites, encephalopathy, spontaneous bacterial peritonitis) increased with severity of AKI. Progression was significantly more common and peak AKI stage higher in nonsurvivors than survivors (P < 0.0001). After adjusting for baseline renal function, demographics, and critical hospital- and cirrhosis-associated variables, progression of AKI was independently associated with mortality (adjusted odds ratio = 3.8, 95% confidence interval 1.3-11.1)., Conclusion: AKI, as defined by AKIN criteria, in patients with cirrhosis is frequently progressive and severe and is independently associated with mortality in a stage-dependent fashion. Methods for earlier diagnosis of AKI and its progression may result in improved outcomes by facilitating targeted and timely treatment of AKI., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Unlabelled: We have previously shown, in a semiquantitative analysis of liver biopsies showing cirrhosis, that thickness of fibrous septa separating cirrhotic nodules and small size of cirrhotic nodules correlated independently with portal pressure (as determined by the hepatic venous pressure gradient; HVPG) and were independent predictors of the presence of clinically significant portal hypertension (PH). This study aimed to confirm these results using quantitative analysis of these biopsies using digital image analysis. Biopsies of 42 patients with cirrhosis and HVPG measurements within 6 months of the biopsy were included in the study. The following parameters were scored quantitatively and without knowledge of HVPG results: total fibrosis area, septal thickness, nodule size, and number of nodules per millimeter of length of liver biopsy. Fibrosis area was the only parameter that independently correlated with HVPG (r = 0.606; P < 0.0001). Correlation was significant, even among patients with clinically significant PH (r = 0.636; P < 0.005). Fibrosis area and nodule size were both independently predictive of the presence of clinically significant PH (r = 0.57; P = 0.003)., Conclusions: On quantitative analysis, fibrosis area was the parameter that correlated best with HVPG and the presence of clinically significant PH. Beyond pathophysiological implications, this also has methodological implications that are discussed in this article., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Acute deterioration of patients with cirrhosis manifests as multiple organ failure requiring admission to an intensive care unit. Precipitating events may be viral hepatitis, typically in Asia, and drug or alcoholic hepatitis and variceal hemorrhage in the West. Patients with cirrhosis in the intensive care unit have a high mortality, and each admission is associated with a mean charge of US $116,200. Prognosis is determined by the number of organs failing (sequential organ failure assessment [SOFA] score), the presence of infection, and the degree of liver dysfunction (Child-Turcotte-Pugh or Model for End-Stage Liver Disease scores). The most common organ failing is the kidney; sepsis is associated with further deterioration in liver function by compromise of the microcirculation. Care of these critically ill patients with impending multiple organ failure requires a team approach with expertise in both hepatology and critical care. Treatment is aimed at preventing further deterioration in liver function, reversing precipitating factors, and supporting failing organs. Liver transplantation is required in selected patients to improve survival and quality of life. Treatment is futile in some patients, but it is difficult to identify these patients a priori. Artificial and bioartificial liver support systems have thus far not demonstrated significant survival benefit in these patients., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Unlabelled: Obesity is associated with an aggressive course in chronic viral hepatitis; however, its impact in the development of clinical decompensation (CD) in patients with established cirrhosis is uncertain. We evaluated the role of obesity, in relationship to other recognized predictors, in the development of CD in patients with compensated cirrhosis. The study population, a subset of patients included in a randomized trial of beta-blockers in the prevention of varices in whom data on body mass index (BMI) was available, consisted of 161 patients with compensated cirrhosis. Laboratory tests and portal pressure (assessed by the hepatic venous pressure gradient or HVPG) were assessed on inclusion. Patients were followed until CD (ascites, hepatic encephalopathy, or variceal hemorrhage), or until September 2002. Altogether, 29% had a normal BMI, 40% were overweight, and 30% were obese. In a median follow-up of 59 months, CD occurred in 48/161 (30%) patients with an increasingly higher rate according to BMI group (15% in those with normal BMI; 31% in overweight; 43% in obese patients, P=0.011). The actuarial probability of developing CD was significantly higher in the abnormal BMI groups (P=0.022). In a multivariate model that included parameters previously identified as being predictive of CD (HVPG, albumin, Mayo endstage liver disease score), etiology, and treatment group, BMI (hazard ration 1.06; 95% confidence interval 1.01-1.12), P=0.02] was an independent predictor of decompensation, together with HVPG and albumin., Conclusion: Obesity has a deleterious effect on the natural history of compensated cirrhosis of all etiologies, independent of portal pressure and liver function. Weight reduction may be a valuable therapeutic measure in this patient population., (Copyright © 2011 American Association for the Study of Liver Diseases.)