Lai, Jennifer C.

Ascites development in cirrhosis reduces 5-year survival from 80% to 30%, yet substantial heterogeneity exists among patients with comparable ascites severity. This multicenter retrospective cohort study included adult liver transplant candidates with ascites at 4 United States centers (2015–2024). Latent class analysis was performed using 7 clinical variables: ascites grade, bilirubin, albumin, platelet count, estimated glomerular filtration rate, systolic blood pressure, and portal vein thrombosis. The derivation cohort (n=625) from the University of California San Francisco and Columbia University was randomly split 80/20 for model development and internal validation. External validation was performed at the University of Southern California (n=59) and Mayo Clinic (n=93). Primary outcomes were acute kidney injury (AKI) and waitlist mortality over 365 days. Three phenotypes emerged: “CKD-Metabolic” (30.4%, lowest eGFR 76.5 mL/min/1.73 m 2 ), “Vasodilatory-Synthetic Dysfunction” (38.9%, highest bilirubin 7.03 mg/dL, lowest blood pressure 117.5 mmHg), and “PVT-Intermediate” (30.7%, severe thrombocytopenia 68.1×10 3 /μL, 24.0% PVT). In validation cohorts (n=305), phenotypes demonstrated robust classification (mean posterior probability 0.823–0.855). Vasodilatory-Synthetic Dysfunction showed increased AKI risk versus CKD-Metabolic in derivation (MELD 3.0-adjusted HR 2.95, 95% CI 2.07–4.22, p <0.001) and validation cohorts (HR 3.39, 95% CI 1.93–5.94, p <0.001). Competing risk analysis revealed no mortality differences, but Vasodilatory-Synthetic Dysfunction was associated with higher transplantation rates (validation: HR 1.63, 95% CI 1.19–2.22, p =0.002). Three reproducible clinical phenotypes of ascites were identified with distinct risk profiles. The Vasodilatory-Synthetic Dysfunction phenotype was associated with a 3-fold increase in the risk of AKI that persisted after adjustment for MELD 3.0. No differences in waitlist mortality were observed, likely reflecting effective MELD-based transplant allocation that preferentially removes the highest-acuity patients from the waitlist.

Background and Aims: Liver transplant is a specialized treatment for a spectrum of indications that use a scarce resource. Transplant is guided by principles of justice, equity, and benefit, with a constant conflict between competing interests. Organs are a national resource with a goal of equitable distribution across sites. An AASLD guideline for the evaluation and selection of appropriate candidates for transplant has been available since 2005. Methods: A multidisciplinary writing group of liver transplant experts and a librarian convened over 24 months. The writing group reviewed the literature, generated guideline recommendations, and rated the level of evidence for each recommendation based on the Oxford Center for Evidence-Based Medicine. The group categorized the strength of recommendations based on the level of evidence, risk-benefit ratio, and patient preferences. Conclusions: Liver transplant is a lifesaving procedure that should be offered to selected patients with clear indications and a reasonable prospect of benefit. The evaluation is designed to identify those in need, to outline hurdles to a successful outcome, and to develop an effective transplant plan. The goal of this document is to provide a template for this process.

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.

Background and Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes, including HE. Androgen receptor agonists, androgen receptor agonists, can address these conditions through multimodal mechanisms of action; however, their safety and efficacy in patients with cirrhosis have not been well established. Approach and Results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral Androgen Receptor Agonist LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary end point was the change from baseline to 24 weeks in skeletal muscle index measured by a CT scan of the L3 region, analyzed with a prespecified modified intent-to-treat population. The secondary end point was the number of overt HE events. Twenty-nine participants (mean age=59 y, MELD=17) received at least 1 dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary end point analysis demonstrated an increase in L3-skeletal muscle index measured by a CT scan of the L3 region in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm2/m2 (95% CI: 1.3–7.4 cm2/m2, p=0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (Common Terminology Criteria for Adverse Events grade ≥2; p=0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms. Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.

The liver transplantation (LT) evaluation and waitlisting process is subject to variations in care that can impede quality. The American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) developed quality measures and patient-reported experience measures along the continuum of pre-LT care to reduce care variation and guide patient-centered care. Following a systematic literature review, candidate pre-LT measures were grouped into 4 phases of care: referral, evaluation and waitlisting, waitlist management, and organ acceptance. A modified Delphi panel with content expertise in hepatology, transplant surgery, psychiatry, transplant infectious disease, palliative care, and social work selected the final set. Candidate patient-reported experience measures spanned domains of cognitive health, emotional health, social well-being, and understanding the LT process. Of the 71 candidate measures, 41 were selected: 9 for referral; 20 for evaluation and waitlisting; 7 for waitlist management; and 5 for organ acceptance. A total of 14 were related to structure, 17 were process measures, and 10 were outcome measures that focused on elements not typically measured in routine care. Among the patient-reported experience measures, candidates of LT rated items from understanding the LT process domain as the most important. The proposed pre-LT measures provide a framework for quality improvement and care standardization among candidates of LT. Select measures apply to various stakeholders such as referring practitioners in the community and LT centers. Clinically meaningful measures that are distinct from those used for regulatory transplant reporting may facilitate local quality improvement initiatives to improve access and quality of care.

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.