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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: Alcohol-associated hepatitis (AH) is associated with significant mortality. Model for End-Stage Liver Disease (MELD) score is used to predict short-term mortality and aid in treatment decisions. MELD is frequently updated in the course of AH. However, once the most updated MELD is known, it is uncertain if previous ones still have prognostic value, which might be relevant for transplant allocation and trial design. We aimed to investigate the predictive performance of updated MELDs in a prospectively collected cohort of patients with AH by the InTeam consortium., Methods: Three hundred seven patients (with 859 MELD values within 60 d of admission) fulfilled the inclusion criteria. The main endpoint was time to death or transplant up to 90 days. We used a joint model approach to assess the predictive value of updated MELDs., Results: Updated MELD measurements had a strong prognostic value for death/transplant (HR: 1.20, 95% CI: 1.14-1.27) (p < 0.0001). Previous MELD values did not add predictive value to the most current MELD. We also showed that MELD at day 28 (MELD28) had a significant predictive value for subsequent mortality/transplant in a landmark analysis (HR: 1.18, 95% CI: 1.12-1.23). We show that the use of an ordinal scale including death, transplant, and MELD28 as a trial outcome could substantially reduce the sample size required to demonstrate short-term benefit of an intervention., Conclusion: We show that updated MELDs during the trajectory of AH predict subsequent mortality or the need for transplant. MELD28 inclusion in an ordinal outcome (together with death or transplant) could increase the efficiency of randomized controlled trials., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Competing Interests: Arpan Mohanty has advised and received grants from Gilead. She received grants from Kinetix Group. The remaining authors have no conflicts to report.

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: Medications for alcohol use disorder (MAUD) are highly effective in achieving and maintaining abstinence in patients with alcohol use disorder (AUD). Our aim was to evaluate the effect of MAUD on all-cause mortality in patients with alcohol-associated cirrhosis and active alcohol use., Methods: This was a retrospective cohort study of patients with alcohol-associated cirrhosis and high-risk alcohol use disorder in the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) database. Propensity score matching for exposure to MAUD (acamprosate or naltrexone) within a year after cirrhosis diagnosis was performed to account for potential confounders, and the association between MAUD and all-cause mortality was subsequently evaluated using Cox regression analysis., Results: A total of 9131 patients were included, of whom 886 (9.7%) were exposed to MAUD (naltrexone: 520, acamprosate: 307, both medications: 59). The duration of MAUD exposure was >3 months in 345 patients (39%). The strongest positive predictor of MAUD prescription was an inpatient diagnosis code for AUD, followed by a concurrent diagnosis of depression; the strongest negative predictor was a history of cirrhosis decompensation. After propensity score matching (866 patients in each group) with excellent covariate balance (absolute standardized mean differences <0.1), MAUD exposure was associated with improved survival, with an HR of 0.80 relative to no MAUD exposure (95% CI: 0.67-0.97, p = 0.024)., Conclusion: MAUD are underutilized in patients with alcohol-associated cirrhosis with high-risk alcohol use behavior but are associated with improved survival after adjustment for confounders such as the severity of liver disease, age, and engagement in the healthcare system., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Clinically significant portal hypertension (CSPH), defined as hepatic venous pressure gradient (HVPG) ≥ 10 mm Hg, identifies patients with compensated cirrhosis at a high risk of decompensation. However, HVPG is an invasive and nuanced method. The ANTICIPATE models, which include liver stiffness measurements by transient elastography (TE) and platelet count ± body mass index, are robust noninvasive surrogates of CSPH but required external validation in patients with nonalcoholic steatohepatitis (NASH) cirrhosis. Additionally, TE is not widely available worldwide. The aims of the study were: (1) to externally validate the ANTICIPATE models using baseline data from patients with compensated NASH cirrhosis screened/enrolled in a multicenter international randomized controlled trial; and (2) to develop and externally validate a model using only laboratory values. Regarding aim 1, both ANTICIPATE models showed good calibration and discrimination (area under the curve [AUC] > 0.8) in our cohort (n = 222). Regarding aim 2, a new lab-based model using the Fibrosis-4 index (FIB-4 [age, aspartate aminotransferase, alanine aminotransferase, platelet count]) plus serum albumin was developed. The discrimination in the training cohort (n = 309) was good (AUC of 0.78 [95% confidence interval [CI]:0.72-0.83]). It was then externally validated in a separate cohort of 245 patients with compensated NASH cirrhosis (AUC of 0.8 [95% CI: 0.75-0.86]). Given the difference in the prevalence of CSPH between training (74%) and validation (39%) cohorts, the model required an update of the baseline risk to achieve a good calibration. The updated model was named FIB4+. In conclusion, both ANTICIPATE models performed well in predicting the presence of CSPH in NASH cirrhosis. A model using FIB-4 plus albumin (FIB4+) can be used to predict CSPH where TE is not available., (© 2022 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Cirrhosis is complicated by a high rate of nosocomial infections (NIs), which result in poor outcomes and are challenging to predict using clinical variables alone. Our aim was to determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multicenter inpatient cirrhosis study, serum was collected on admission for liquid chromatography-mass spectrometry metabolomics, and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death, were analyzed. Metabolomic analysis using analysis of covariance (ANCOVA) (demographics, Model for End-Stage Liver Disease [MELD] admission score, white blood count [WBC], rifaximin, and infection status adjusted) and random forest analyses for NI development were performed. Additional values of serum metabolites over clinical variables toward NI were evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with and without NI development. A total of 602 patients (231 infection admissions) were included; 101 (17%) developed NIs, which resulted in worse inpatient outcomes, including intensive care unit transfer, organ failure, and death. A total of 127 patients also gave stool samples, and 20 of these patients developed NIs. The most common NIs were spontaneous bacterial peritonitis followed by urinary tract infection, Clostridioides difficile, and pneumonia. A total of 247 metabolites were significantly altered on ANCOVA. Higher MELD scores (odds ratio, 1.05; p < 0.0001), admission infection (odds ratio, 3.54; p < 0.0001), and admission WBC (odds ratio, 1.05; p = 0.04) predicted NI (area under the curve, 0.74), which increased to 0.77 (p = 0.05) with lower 1-linolenoyl-glycerolphosphocholine (GPC) and 1-stearoyl-GPC and higher N-acetyltryptophan and N-acetyl isoputreanine. Commensal microbiota were lower and pathobionts were higher in those who developed NIs. Microbial-metabolite correlation networks were complex and dense in patients with NIs, especially sub-networks centered on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in patients with NIs showed higher pathobionts and lower commensal microbiota. Microbial-metabolomic correlations were more complex, dense, and homogeneous among those who developed NIs, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis., (© 2022 American Association for the Study of Liver Diseases.)

Content available: Author Interview and Audio Recording., (© 2021 by the 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.)

Content available: Author Audio Recording., (© 2021 American Association for the Study of Liver Diseases. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

The 10-item Alcohol Use Disorders Identification Test (AUDIT-10) and its shorter form, AUDIT-Consumption (AUDIT-C), are questionnaires used to characterize severity of drinking. We hypothesized that liver injury and short-term outcomes of alcohol-associated hepatitis (AH) would correlate with a patient's recent alcohol consumption as determined by AUDIT-10 and AUDIT-C. We analyzed a prospective international database of patients with AH diagnosed based on the National Institute on Alcohol Abuse and Alcoholism (NIAAA) standard definitions. All patients were interviewed using AUDIT-10. Primary outcomes included the discriminatory ability of the AUDIT-10 and AUDIT-C scores for predicting survival status at 28 and 90 days and severity of liver injury, as measured by Model for End-Stage Liver Disease-sodium (MELD-Na). The relationship between AUDIT scores and survival status was quantified by calculating the area under the curve of the receiver operating characteristic analysis. The relationship between AUDIT scores and MELD-Na was examined using correlation coefficients. In 245 patients (age range 25-75 years; 35% female), we found no correlation between AUDIT-10 or AUDIT-C scores and either 28- or 90-day mortality. Similarly, there was no correlation between AUDIT-10 and AUDIT-C and MELD-Na scores. There was a strong positive correlation between MELD-Na and 28- and 90-day mortality. Additional measures of severity of alcohol use (average grams of alcohol consumed per day, years of drinking, convictions for driving under the influence, and rehabilitation attempts) and psychosocial factors (marriage, paid employment, and level of social support) had no influence on MELD-Na. In patients presenting with AH, AUDIT-10 and AUDIT-C were predictors of neither clinical severity of liver disease nor short-term mortality, suggesting that level of alcohol consumption in the prior year is not key to the presenting features or outcome of AH., (Copyright © 2021 by the American Association for the Study of Liver Diseases.)

The intestinal microbiome and bacterial translocation (BT), the passage of microorganisms from the gut lumen to mesenteric lymph nodes and other extra-intestinal sites, are main mechanisms implicated in liver injury and further decompensation in patients with cirrhosis. We hypothesized that obeticholic acid (OCA), a semisynthetic bile acid, would change the microbiome composition and reduce bacterial translocation in experimental cirrhosis. Rats with cirrhosis induced by carbon tetrachloride inhalation (a nonseptic model) with ascites present for at least 7 days were randomized to receive a 14-day course of OCA at a dose of 5 mg/kg/day (n = 34) or placebo (n = 34). Stool was collected at days 1 (randomization), 8, and 14 (sacrifice) for analysis of intestinal microbiome using the V4 hypervariable region of the bacterial 16S gene amplified by polymerase chain reaction. Bacteriological cultures of mesenteric lymph nodes, blood, and ascites were performed at end of study. Twenty-four animals in each group reached the end of study. Compared with placebo, rats treated with OCA had decreased relative abundance of Enterococcus in both ileum content (P = 0.02) and in stool (P < 0.001). BT from pathogenic bacteria was not different between groups. At end of treatment, rats on OCA had a significantly lower aspartate aminotransferase (AST) (266 vs. 369 IU/L; P < 0.01) and higher serum albumin (0.9 vs. 0.7 g/dL; P < 0.01) than rats on placebo. Conclusion: Although OCA did not appear to reduce BT by pathogenic bacteria, the reduction in intestinal content of Enterococcus, which has been associated with hepatocyte death, in OCA-treated animals is consistent with our observed improvements in AST and in liver function, as evidenced by higher serum albumin., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

Disturbed sleep is common among patients with cirrhosis. The extent to which this is associated with the different stages of compensated cirrhosis is unknown. This study examines whether the presence of portosystemic collaterals, an indicator of clinically significant portal hypertension, is associated with sleep disturbance in compensated cirrhosis. We conducted a cross-sectional study among patients with compensated cirrhosis, comparing sleep characteristics, sleep quality, and excessive daytime sleepiness between 21 patients without and 21 patients with portosystemic collaterals. Patients were assessed with wrist actigraphy, Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale. Collateral presence was determined by imaging and esophagogastroduodenoscopy. Differences in sleep characteristics were analyzed using t tests and computed effect sizes. Multivariable linear regression analysis was used to evaluate the association between collaterals and sleep disturbance while controlling for possible confounders. The group of patients with collaterals had greater beta-blocker and tobacco use, lower albumin, and higher international normalized ratio compared to the group without collaterals. Patients with collaterals had more sleep fragmentation (Cohen's d  = -0.86), lower sleep efficiency (Cohen's d  = 0.59), and lower total sleep time (Cohen's d  = 0.75) than patients without collaterals. The presence of collaterals was independently associated with greater sleep fragmentation ( P  = 0.046) and greater daytime sleepiness ( P  = 0.030). Conclusion: Patients with compensated cirrhosis complicated by portosystemic collaterals experienced more sleep disturbance than those without collaterals., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.)

In patients with decompensated cirrhosis, procedure-related bleeding is a potentially lethal complication. Routine coagulation tests such as international normalized ratio and platelet count do not predict bleeding risk. We investigated whether thromboelastography (TEG) can identify patients with cirrhosis who are at risk of procedure-related bleeding. As a part of a prospective study on hemostasis in decompensated cirrhosis, patients had TEG performed on admission and were followed prospectively during hospitalization for the development of procedure-related bleeding. Eighty patients with cirrhosis were included. Among the 72 who had procedures performed, 7 had procedure-related bleeding, which was major in three cases (two following paracentesis and one following thoracentesis). Conventional coagulation tests were comparable between bleeding and nonbleeding patients, whereas TEG parameters of k-time (4.5 minutes vs. 2.2 minutes; P  = 0.02), α-angle (34° vs. 59°; P  = 0.003), and maximum amplitude (37 mm vs. 50 mm; P  = 0.004) were significantly different (all indicative of hypocoagulability). TEG maximum amplitude (MA), a marker of overall clot stability, accurately discriminated between patients who had major, life-threatening bleeding (all with MA < 30 mm) and those who had mild or no bleeding (all with MA > 30 mm), whereas a platelet count < 50 × 10 9 /L could not discriminate between bleeding (minor or major) and nonbleeding patients. Conclusion : In a prospective cohort of hospitalized patients with decompensated cirrhosis, TEG parameters associated with hypocoagulability appeared to predict procedure-related bleeding, particularly a TEG MA < 30 mm. If results are validated in a larger cohort, this could be a threshold to identify patients with decompensated cirrhosis at higher risk for procedure-related bleeding, in whom to consider preprocedural prophylaxis., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of 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.)

#LiverTwitter has emerged as an academic forum that has begun to advance the field of hepatology by disseminating content on chronic liver diseases to a global audience. This article summarizes the content presented in a panel discussion at the 2019 Liver Meeting by highlighting the perspectives of several key types of participants in Twitter: the trainee, the medical educator, the divisional account, the scientific journal, and the passive participant., (© 2020 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of 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.)

We hypothesize that the prevalence of chronic kidney disease (CKD) among patients with cirrhosis has increased due to the increased prevalence of CKD-associated comorbidities, such as diabetes. We aimed to assess the characteristics of hospitalized patients with cirrhosis with CKD and its impact on renal and patient outcomes. The North American Consortium for the Study of End-Stage Liver Disease (NACSELD) prospectively enrolled nonelectively admitted patients with cirrhosis and collected data on demographics, laboratory results, in-hospital clinical course, and postdischarge 3-month outcomes. CKD positive (CKD+) patients, defined as having an estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease-4 variable formula) of ≤60 mL/minute for >3 months, were compared with chronic kidney disease negative (CKD-) patients for development of organ failures, hospital course, and survival. There were 1099 CKD+ patients (46.8% of 2346 enrolled patients) who had significantly higher serum creatinine (2.21 ± 1.33 versus 0.83 ± 0.21 mg/dL in the CKD- group) on admission, higher prevalence of nonalcoholic steatohepatitis cirrhosis etiology, diabetes, refractory ascites, and hospital admissions in the previous 6 months compared with the CKD- group (all P < 0.001). Propensity matching (n = 922 in each group) by Child-Pugh scores (9.78 ± 2.05 versus 9.74 ± 2.04, P = 0.70) showed that CKD+ patients had significantly higher rates of superimposed acute kidney injury (AKI; 68% versus 21%; P < 0.001) and eventual need for dialysis (11% versus 2%; P < 0.001) than CKD- patients. CKD+ patients also had more cases of acute-on-chronic liver failure as defined by the NACSELD group, which was associated with reduced 30- and 90-day overall survival (P < 0.001 for both). A 10 mL/minute drop in eGFR was associated with a 13.1% increase in the risk of 30-day mortality. In conclusion, patients with CKD should be treated as a high-risk group among hospitalized patients with cirrhosis due to their poor survival, and they should be monitored carefully for the development of superimposed AKI., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Acute-on-chronic liver failure (ACLF) characterized with ≥2 extrahepatic organ failures in cirrhosis carries a high mortality. Outcomes of patients listed for liver transplantation (LT) after ACLF and after LT are largely unknown. The North American Consortium for the Study of End-Stage Liver Disease prospectively enrolled 2793 nonelectively hospitalized patients with cirrhosis; 768 were listed for LT. Within 3 months, 265 (35%) received a LT, 395 remained alive without LT, and 108 died/delisted. Compared with nonlisted patients, those listed were younger and more often had ACLF, acute kidney injury, and a higher admission Model for End-Stage Liver Disease (MELD) score. ACLF was most common in patients who died/delisted, followed by those alive with and without LT respectively, (30%, 22%, and 7%, respectively; P < 0.001). At LT, median MELD was 27.9% and 70% were inpatients; median time from hospitalization to LT was 26 days. Post-LT survival at 6 months was unchanged between those with and without ACLF (93% each at 6 months). There was no difference in 3- and 6-month mean post-LT creatinine in those with and without ACLF, despite those with ACLF having a higher mean pre-LT creatinine and a higher rate of perioperative dialysis (61%). In conclusion, patients with and without ACLF had similar survival after transplant with excellent renal recovery in both groups., (Copyright © 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.)

It is a commentary intended to outline and try to clarify some of the issues that have led to confusion in the field regarding acute-on-chronic liver failure.

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.)

Goals/background: Data on acute variceal hemorrhage (AVH) in the United States is limited and the best method to stratify risk is not clear. Taking advantage of a prospective US cohort study, we aimed to (1) describe clinical outcomes of AVH and their predictors; (2) compare predictors of 6-week mortality., Study: Prospective 15-center US cohort of patients with cirrhosis presenting with endoscopically proven AVH, all of whom received antibiotics, vapreotide (a somatostain analog) infusion and endoscopic band ligation. Patients were enrolled between August 2006 and April 2008. Primary outcome was 6-week mortality. Secondary outcome was 5-day treatment failure. The prognostic value of Child-Turcotte-Pugh (CTP) class, Model for End-stage Liver Disease (MELD) score and a recent recalibrated MELD were compared., Results: Seventy eligible patient were enrolled; 18 (26%) patients died within 6-weeks of index bleed. Demographic, clinical, and laboratory data were compared between survivors and nonsurvivors. Multivariate models showed that admission CTP or the MELD score (separately) were independent predictors of survival. The discriminative values of CTP (area under receiver operating characteristic: 0.75) and MELD (area under receiver operating characteristic: 0.79) were good and not significantly different (P=0.27). However, calibration (correlation between observed and predicted mortality) test was significantly better for CTP than for MELD, with the recently described recalibrated MELD model having the worst agreement. Predicted mortality for CTP-A was <10%, CTP-B 10% to 30%; and CTP-C >33%., Conclusions: AVH mortality of 26% in the United States is in the upper range limit compared with recent series but may be due to inclusion of patients with more advanced cirrhosis. CTP score has the best overall performance in the prediction of 6-week mortality and is best at stratifying risk.