Citations

INTRODUCTION: A Model for End-Stage Liver Disease-lactate (MELD-LA) score is an independent predictor of inpatient mortality and organ failure validated in more than 8,600 patients across diverse settings. However, its utility in sepsis, particularly when combined with lactate clearance (LA clearance), has not been fully evaluated. In this study, we examined the dynamic role of MELD-LA with 24-hour LA clearance as a predictor of 30-day mortality in critically ill patients with cirrhosis and sepsis. METHODS: We analyzed cirrhosis patients with sepsis admitted to the intensive care unit (ICU) in a large US healthcare system (20 hospitals) from 2014 to 2022, examining MELD-LA and LA clearance within 24 hours as predictors of 30-day mortality. We externally validated our findings in the Asian Pacific Association for the Study of the Liver-acute-on-chronic liver failure Research Consortium, a multinational Asian cohort (31 centers) from 2009 to 2019. RESULTS: A total of 3,879 cirrhosis patients with sepsis were admitted to the ICU (43.2% female, 20.5% Hispanic, 12.4% on dialysis; mean initial LA 4.5 mmol/L, MELD 20.8, MELD-LA 17.6). Survivors showed a median lactate change of −1.04 (35% clearance) compared with −0.4 (12%) for nonsurvivors. LA clearance within 24 hours was influenced by the presenting MELD-LA. In the North American cohort, ≥35% LA clearance was associated with improved 30-day survival (odds ratio 0.41, 95% CI 0.31–0.53; P < 0.001). Similarly, in the Asian Pacific Association for the Study of the Liver cohort (n = 1,259), ≥35% clearance was linked to a 60% reduction in mortality (odds ratio 0.42, 95% CI 0.28–0.62; P < 0.001). When stratified by LA clearance, patients with LA clearance of ≥35% had a higher percentage of early administration of resuscitative measures than those with LA clearance of < 10% especially regarding early antibiotic administration (82.5% vs 67.6%; P value <0.001). DISCUSSION: Early reduction in initial LA by one-third predicts 30-day mortality and may indicate treatment response in cirrhosis patients with sepsis in the ICU. Combining MELD-LA and LA clearance early enables better risk stratification and informs management.

Background and Aims: Prognosticating outcomes such as hospitalizations in outpatients with cirrhosis is challenging, especially with changing etiologies and demographics. This study aims to determine the impact of multi-omic strategies on outcome prediction. Approach and Results: NACSELD3 enrolls outpatients with cirrhosis with controlled/eradicated etiologies from 10 centers and follows them systematically. At baseline, clinical/demographic and cirrhosis details were recorded and saliva and serum samples were collected for microbiome and metabolome analysis, respectively. Multi-omic bioinformatic studies to determine the interaction of microbiota and metabolites with the clinical prediction of 6-month hospitalizations were performed. Five hundred sixty-five patients (60.2 y, 68% men, 35% alcohol, 33% metabolic dysfunction-associated steatohepatitis, 21%, eradicated HCV with MELD 3.0 12) were enrolled. One hundred sixty-three (29%) required 6-month hospitalizations; most (75%) were liver-related. Those hospitalized had worse cirrhosis severity and comorbidity indices but similar demographics and oral health variables. Salivary microbiome alpha-diversity was lower (1.96±0.48 vs. 2.09±0.45, p =0.018) with greater pathobionts ( Streptococcus , Treponema, Enterococcaceae) and lower commensal genhospitalized/noera ( Veillonella, Prevotella, Haemophilus , Lachnospiraceae spp) at baseline. Serum metabolomics showed significant separation at baseline between hospitalized/non-hospitalized patients using supervised analyses with microbial-origin (phenyllactate, secondary bile acids, indoles), choline moieties, and polyamine/GABA (3-ureidopropionate/spermidine) metabolites being most prominent. Area under the curve using random forest for clinical, microbial, and metabolomic variables was higher than that of these individually. Latent factor analysis showed clinical variables (MELD 3.0, hemoglobin, and albumin) with the greatest impact, followed by salivary microbiota and then serum microbiome for hospitalization prediction. Conclusions: In a multicenter North American outpatient cirrhosis cohort with controlled etiologies, serum metabolomics and salivary microbiome add to clinical variables to prognosticate 6-month hospitalization.

INTRODUCTION: Perception of the ascites burden and its effects on quality of life may be different between sexes. This study assessed sex differences in perception of ascites burden and its impact on health-related quality of life (HRQoL) in patients with recurrent or refractory ascites. METHODS: The North American Consortium for the Study of End-stage Liver Disease prospectively enrolled outpatients with cirrhosis and large ascites requiring repeat large volume paracenteses. Demographics, laboratory results, comorbidities, medications, frailty measurements, and self-reported questionnaires related to functional status, physical activities, and HRQoL (generic = Short Form 36 and ascites specific = Ascites Questionnaire) were compared between sexes. RESULTS: In total, 392 men (59.6 ± 10.7 years) and 184 women (59.5 ± 11.1 years) with predominantly alcohol-related liver disease (51% and 43%, respectively) and median Model for End-Stage Liver Disease-Na: 13 were enrolled. Both groups had similar comorbidities and cirrhosis complications, ascites duration and severity, and frailty scores ( P = 0.94). Women had more symptoms related to their ascites (Ascites Questionnaire score = 66 ± 21 vs 60 ± 21 in men, P = 0.001) (higher value = feeling worse). 35% of women felt depressed vs 22% of men ( P = 0.0009), with lower mental but not physical functioning components of Short Form 36 ( P = 0.019). Women continued to conduct their daily activities as adequately as men as indicated by Duke Status Activity Index ( P = 0.27) and Godin Leisure Activity Index ( P = 0.47). DISCUSSION: Women with cirrhosis and ascites experienced worse emotional HRQoL than men without difference in daily function. Our analyses underscore the differences in the lived experience of women vs men with cirrhosis and highlight the need for patient-reported metrics to provide patient-centered care.

Abstract TIGIT (T cell immunoreceptor with Ig and ITIM domains) is a co-inhibitory receptor, highly expressed by Tregs, and contributes to the suppressive function of Tregs by limiting pro-inflammatory Th1 and Th17 cell responses. Herein, we report that subsets of human regulatory B cells (Bregs) express surface TIGIT and can thus play a critical role in immune regulation. Using data from human B cell surface arrays and RNA-seq, we identified two major TIGIT+ human Bregs subsets, exhibiting CD24hiCD27+CD39hiIgD+IgMhiCD1chi marginal zone (MZ)-like and CD24hiCD27+CD39+IgD−IgM+CD1c+ memory Bregs. We further demonstrated that TIGIT+ Bregs were also capable of suppressing immune responses by their ability to express not only IL-10 and PD-L1, but also granzyme B and TGFb1. In addition, TIGIT+ Bregs can also suppress immune responses by altering dendritic cell functions. In line with these observations, liver allograft recipients with donor-specific alloantibody (DSA) had significantly lower numbers of TIGIT+ Bregs than those without DSA. Moreover, the frequency of TIGIT+ Bregs correlated with that of CD4+CD25+CD127lo Tregs, while it inversely correlated with the frequency of follicular helper T cells. We thus concluded that TIGIT+ Bregs play critical roles in immune regulation in liver allograft recipients.

Abstract 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.

AbstractBackgroundThe prognosis of acute kidney disease (AKD), defined as a glomerular filtration rate of <60 ml/min/1.73 m2 or a rise in serum creatinine (sCr) of <50% for <3 months, is not clearly known.AimTo study the prevalence, predictive factors and clinical outcomes in hospitalized cirrhotic patients with AKD.MethodsThe North American Consortium for the Study of End‐Stage Liver Disease prospectively enrolled hospitalized decompensated cirrhotic patients. Patients were separated into those with normal renal function (controls or C), AKD or stage 1 AKI as their worst renal dysfunction per International Club of Ascites definition and compared. Parameters assessed included demographics, laboratory data, haemodynamics, renal and patient outcomes.Results1244 patients with cirrhosis and ascites (C: 704 or 57%; AKD: 176 or 14%; stage 1 AKI: 364 or 29%) with similar demographics were enrolled. AKD patients had similar baseline sCr but higher hospital admission in the previous 6 months, and higher peak sCr, compared to controls, with their peak sCr being lower than that in stage 1 AKI patients (all P < .0001). The in‐hospital and 30‐day survival for AKD patients were intermediary between that for controls and stage 1 AKI patients (96% vs 91% vs 86%, P < .0001). The strongest predictors for AKD development while in hospital were the presence of a second infection (OR: 2.44) and diabetes (OR: 1.53).ConclusionsPatients with AKD had intermediate outcomes between stage 1 AKI and controls. AKD patients, especially those with diabetes and a second infection, need careful monitoring and prompt treatment for AKD to prevent negative outcomes.

In patients with cirrhosis and chronic liver disease, acute-on-chronic liver failure is emerging as a major cause of mortality. These guidelines indicate the preferred approach to the management of patients with acute-on-chronic liver failure and represent the official practice recommendations of the American College of Gastroenterology. The scientific evidence for these guidelines was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation process. In instances where the evidence was not appropriate for Grading of Recommendations, Assessment, Development, and Evaluation, but there was consensus of significant clinical merit, key concept statements were developed using expert consensus. These guidelines are meant to be broadly applicable and should be viewed as the preferred, but not only, approach to clinical scenarios.