Liver transplantation provides survival benefit at all levels of frailty: From the Multicenter Functional Assessment in Liver Transplantation Study.

BACKGROUND AND AIMS: Offering LT to frail patients may reduce waitlist mortality but may increase post-LT mortality. LT survival benefit is the concept of balancing these risks. We sought to quantify the net survival benefit with LT by liver frailty index (LFI). APPROACH AND RESULTS: We analyzed data in the multicenter Functional Assessment in LT (FrAILT) study from 2012 to 2021. Pre-LT cohort included ambulatory patients with cirrhosis awaiting LT, without HCC; the post-LT cohort included those who underwent LT. Primary outcomes were pre-LT and post-LT mortality. We computed 1-, 3-, and 5-year restricted mean survival times (RMSTs) from adjusted Cox models. The survival benefit was calculated as a net gain in life-years with LT. Pre-LT cohort included 2628 patients: median Model for End-Stage Liver Disease-Sodium was 18 (IQR: 14-22); 731 (28%) were frail; 440 (17%) died before LT. Post-LT cohort included 1335 patients: median Model for End-Stage Liver Disease-Sodium was 20 (IQR: 14-24); 325 (24%) were frail; 103 (8%) died after LT. Pre-LT RMST decreased substantially as LFI increased. Post-LT RMST also decreased as LFI increased but only modestly. There was no LFI threshold at which pre-LT and post-LT RMST intersected-patients had net survival benefits at all LFI values. CONCLUSIONS: Pre-LT and, to a lesser degree, post-LT mortality increased as LFI increased. Transplant offered a survival benefit at all LFI values, driven by a reduction in pre-LT mortality. No threshold of LFI was identified at which the risk of post-LT mortality exceeded pre-LT mortality. LT offers net survival benefits even in the presence of advanced frailty among those selected for LT.

Quality measures in pre-liver transplant care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

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.

Metabolic Engineering: Methodologies and Applications.

Metabolic engineering aims to improve the production of economically valuable molecules through the genetic manipulation of microbial metabolism. While the discipline is a little over 30 years old, advancements in metabolic engineering have given way to industrial-level molecule production benefitting multiple industries such as chemical, agriculture, food, pharmaceutical, and energy industries. This review describes the design, build, test, and learn steps necessary for leading a successful metabolic engineering campaign. Moreover, we highlight major applications of metabolic engineering, including synthesizing chemicals and fuels, broadening substrate utilization, and improving host robustness with a focus on specific case studies. Finally, we conclude with a discussion on perspectives and future challenges related to metabolic engineering.

Patient-centered care: Key elements applicable to chronic liver disease.

Chronic liver disease (CLD) is a progressive illness with high symptom burden and functional and cognitive impairment, often with comorbid mental and substance use disorders. These factors lead to significant deterioration in quality of life, with immense burden on patients, caregivers, and healthcare. The current healthcare system in the United States does not adequately meet the needs of patients with CLD or control costs given the episodic, reactive, and fee-for-service structure. There is also a need for clinical and financial accountability for CLD care. In this context, we describe the key elements required to shift the CLD care paradigm to a patient-centered and value-based system built upon the Porter model of value-based health care. The key elements include (1) organization into integrated practice units, (2) measuring and incorporating meaningful patient-reported outcomes, (3) enabling technology to allow innovation, (4) bundled care payments, (5) integrating palliative care within routine care, and (6) formalizing centers of excellence. These elements have been shown to improve outcomes, reduce costs, and improve overall patient experience for other chronic illnesses and should have similar benefits for CLD. Payers need to partner with providers and systems to build upon these elements and help align reimbursements with patients' values and outcomes. The national organizations such as the American Association for Study of Liver Diseases need to guide key stakeholders in standardizing these elements to optimize patient-centered care for CLD.

The liver frailty index is a predictor of healthcare utilization after liver transplantation in older adults.

BACKGROUND: Older adults have higher healthcare utilization after liver transplantation (LT), yet objective risk stratification tools in this population are lacking. We evaluated the Liver Frailty Index (LFI) as one potential tool. METHODS: Ambulatory LT candidates ≥65 years without hepatocellular carcinoma (HCC) who underwent LT from 1/2012 to 6/2022 at 8 U.S. centers were included. Estimates of the difference in median using quantile regression were used to assess the adjusted association between LFI and hospitalized days within 90 days post-LT. RESULTS: Of 131 LT recipients, median (interquartile range [IQR]) (1st -3rd quartiles) age was 68 years (66-70); median pre-LT MELD-Na was 19 (15-24). Median LFI was 4.1 (3.6-4.7); 27% were frail (LFI≥4.5). Median hospitalized days within 90 days post-LT was 11 (7-20). Compared with non-frail patients, frail patients were hospitalized for a median of 5 days longer post-LT (95% CI .30-9.7, p = .04). Each .5 unit increase in pre-LT LFI was associated with an increase of 1.16 days (95%CI .42-2.69, p = .02) in hospitalized days post-LT. CONCLUSION: Among older adults undergoing LT, frailty was associated with more hospitalized days within 90 days after LT. The LFI can identify older adults who might benefit from pre-LT or early post-LT programs which may reduce post-LT healthcare utilization, such as early rehabilitation or post-hospital discharge programs.

Association of body mass index with post-liver transplant outcomes.

BACKGROUND: Patients with obesity have inferior outcomes after general surgery procedures, but studies evaluating post-liver transplant (LT) outcomes have been limited by small sample sizes or lack of granularity of outcomes. We evaluated the relationship between obesity and post-LT outcomes, including those observed in other populations to be obesity-related. METHODS: Included were 1357 LT recipients prospectively enrolled in the ambulatory pre-LT setting at 8 U.S. CENTERS: Recipient were categorized by body mass index (BMI, kg/m2 ): non-obese (BMI < 30), class 1 obesity (BMI 30-<35), and classes 2-3 obesity (BMI ≥ 35). Post-transplant complications were compared by BMI using Chi-square and rank-sum testing, logistic regression, Kaplan-Meier curves, and Cox regression. RESULTS: Classes 2-3 obesity was associated with higher adjusted odds than non-obesity of venous thrombosis [adjusted odds ratio (aOR) 2.06, 95% CI 1.01-4.23, p = .047] and wound dehiscence (aOR 2.45, 95% CI 1.19-5.06, p = .02). Compared with non-obese recipients, post-LT hospital stay was significantly longer for recipients with classes 2-3 obesity [p = .01; median (Q1-Q3) 9 (6-14) vs. 8 (6-12) days) or class 1 obesity [p = .002; 9 (6-14) vs. 8 (6-11) days].  Likelihood of ICU readmission, infection, discharge to a non-home facility, rejection, 30-day readmission, and 1-year readmission were similar across BMI categories (all p > .05). CONCLUSION: Compared to non-obese recipients, obese recipients had similar post-LT survival but longer hospital stay and higher likelihood of wound dehiscence and venous thrombosis. These findings underscore that obesity alone should not preclude LT, but recipients with obesity should be monitored for obesity-related complications such as wound dehiscence and venous thrombosis.

Proton beam radiotherapy versus transarterial chemoembolization for hepatocellular carcinoma: Results of a randomized clinical trial.

BACKGROUND: This study compares survival rates, recurrence patterns, toxicity, and treatment cost in patients with hepatocellular carcinoma (HCC) treated with either transarterial chemoembolization (TACE) or proton beam radiotherapy (PBT). METHODS: Subjects with untreated HCC meeting Milan or San Francisco transplant criteria were recruited. Subjects were randomized to receive PBT (n = 36) or TACE (n = 40). Proton therapy was administered in 15 fractions over 3 weeks to a total dose of 70.2 Gy. TACE was repeated until complete or maximal response. The primary outcome measure was overall survival (OS). Secondary end points were progression-free survival (PFS), local control (LC), toxicity, and cost. RESULTS: Of the 76 randomized patients, 74 were assessed for outcome measures. The 2-year OS for PBT versus TACE was similar at 68%, 95% confidence interval (CI), 0.54-0.86, and 65%, 95% CI, 0.52-0.83 (p = .80), however, median PFS was improved for PBT versus TACE (not reached vs. 12 months, p = .002). LC was improved with PBT versus TACE (hazard ratio, 5.64; 95% CI, 1.78-17.9, p = .003). Days of posttreatment hospitalization were 24 for PBT and 166 for TACE (p < .001). Total mean cost per patient for treatment and posttreatment care revealed a 28% cost savings for PBT. CONCLUSIONS: PBT and TACE yielded similar OS for treatment of HCC, but PFS and LC were improved with PBT compared to TACE. Patients treated with PBT required fewer courses of treatment, fewer posttreatment hospitalization days, and reduced cost of treatment compared to TACE. These data support the use of PBT as a viable treatment alternative to TACE for patients with HCC within transplant criteria.

Design and application of a kinetic model of lipid metabolism in Saccharomyces cerevisiae.

Lipid biosynthesis plays a vital role in living cells and has been increasingly engineered to overproduce various lipid-based chemicals. However, owing to the tightly constrained and interconnected nature of lipid biosynthesis, both understanding and engineering of lipid metabolism remain challenging, even with the help of mathematical models. Here we report the development of a kinetic metabolic model of lipid metabolism in Saccharomyces cerevisiae that integrates fatty acid biosynthesis, glycerophospholipid metabolism, sphingolipid metabolism, storage lipids, lumped sterol synthesis, and the synthesis and transport of relevant target-chemicals, such as fatty acids and fatty alcohols. The model was trained on lipidomic data of a reference S. cerevisiae strain, single knockout mutants, and lipid overproduction strains reported in literature. The model was used to design mutants for fatty alcohol overproduction and the lipidomic analysis of the resultant mutant strains coupled with model-guided hypothesis led to discovery of a futile cycle in the triacylglycerol biosynthesis pathway. In addition, the model was used to explain successful and unsuccessful mutant designs in metabolic engineering literature. Thus, this kinetic model of lipid metabolism can not only enable the discovery of new phenomenon in lipid metabolism but also the engineering of mutant strains for overproduction of lipids.

Frailty, mortality, and health care utilization after liver transplantation: From the Multicenter Functional Assessment in Liver Transplantation (FrAILT) Study.

BACKGROUND AND AIMS: Frailty is a well-established risk factor for poor outcomes in patients with cirrhosis awaiting liver transplantation (LT), but whether it predicts outcomes among those who have undergone LT is unknown. APPROACH AND RESULTS: Adult LT recipients from 8 US centers (2012-2019) were included. Pre-LT frailty was assessed in the ambulatory setting using the Liver Frailty Index (LFI). "Frail" was defined by an optimal cut point of LFI ≥ 4.5. We used the 75th percentile to define "prolonged" post-LT length of stay (LOS; ≥12 days), intensive care unit (ICU) days (≥4 days), and inpatient days within 90 post-LT days (≥17 days). Of 1166 LT recipients, 21% were frail pre-LT. Cumulative incidence of death at 1 and 5 years was 6% and 16% for frail and 4% and 10% for nonfrail patients (overall log-rank p = 0.02). Pre-LT frailty was associated with an unadjusted 62% increased risk of post-LT mortality (95% CI, 1.08-2.44); after adjustment for body mass index, HCC, donor age, and donation after cardiac death status, the HR was 2.13 (95% CI, 1.39-3.26). Patients who were frail versus nonfrail experienced a higher adjusted odds of prolonged LT LOS (OR, 2.00; 95% CI, 1.47-2.73), ICU stay (OR, 1.56; 95% CI, 1.12-2.14), inpatient days within 90 post-LT days (OR, 1.72; 95% CI, 1.25-2.37), and nonhome discharge (OR, 2.50; 95% CI, 1.58-3.97). CONCLUSIONS: Compared with nonfrail patients, frail LT recipients had a higher risk of post-LT death and greater post-LT health care utilization, although overall post-LT survival was acceptable. These data lay the foundation to investigate whether targeting pre-LT frailty will improve post-LT outcomes and reduce resource utilization.

Patient-reported outcomes in HCC: A scoping review by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

BACKGROUND AND AIMS: HCC is a leading cause of mortality in patients with advanced liver disease and is associated with significant morbidity. Despite multiple available curative and palliative treatments, there is a lack of systematic evaluation of patient-reported outcomes (PROs) in HCC. APPROACH AND RESULTS: The American Association for the Study of Liver Diseases Practice Metrics Committee conducted a scoping review of PROs in HCC from 1990 to 2021 to (1) synthesize the evidence on PROs in HCC and (2) provide recommendations on incorporating PROs into clinical practice and quality improvement efforts. A total of 63 studies met inclusion criteria investigating factors associated with PROs, the relationship between PROs and survival, and associations between HCC therapy and PROs. Studies recruited heterogeneous populations, and most were cross-sectional. Poor PROs were associated with worse prognosis after adjusting for clinical factors and with more advanced disease stage, although some studies showed better PROs in patients with HCC compared to those with cirrhosis. Locoregional and systemic therapies were generally associated with a high symptom burden; however, some studies showed lower symptom burden for transarterial radiotherapy and radiation therapy. Qualitative studies identified additional symptoms not routinely assessed with structured questionnaires. Gaps in the literature include lack of integration of PROs into clinical care to guide HCC treatment decisions, unknown impact of HCC on caregivers, and the effect of palliative or supportive care quality of life and health outcomes. CONCLUSION: Evidence supports assessment of PROs in HCC; however, clinical implementation and the impact of PRO measurement on quality of care and longitudinal outcomes need future investigation.

Quality measures in HCC care by the Practice Metrics Committee of the American Association for the Study of Liver Diseases.

The burden of HCC is substantial. To address gaps in HCC care, the American Association for the Study of Liver Diseases (AASLD) Practice Metrics Committee (PMC) aimed to develop a standard set of process-based measures and patient-reported outcomes (PROs) along the HCC care continuum. We identified candidate process and outcomes measures for HCC care based on structured literature review. A 13-member panel with content expertise across the HCC care continuum evaluated candidate measures on importance and performance gap using a modified Delphi approach (two rounds of rating) to define the final set of measures. Candidate PROs based on a structured scoping review were ranked by 74 patients with HCC across 7 diverse institutions. Out of 135 measures, 29 measures made the final set. These covered surveillance (6 measures), diagnosis (6 measures), staging (2 measures), treatment (10 measures), and outcomes (5 measures). Examples included the use of ultrasound (± alpha-fetoprotein [AFP]) every 6 months, need for surveillance in high-risk populations, diagnostic testing for patients with a new AFP elevation, multidisciplinary liver tumor board (MLTB) review of Liver Imaging-Reporting and Data System 4 lesions, standard evaluation at diagnosis, treatment recommendations based on Barcelona Clinic Liver Cancer staging, MLTB discussion of treatment options, appropriate referral for evaluation of liver transplantation candidacy, and role of palliative therapy. PROs include those related to pain, anxiety, fear of treatment, and uncertainty about the best individual treatment and the future. The AASLD PMC has developed a set of explicit quality measures in HCC care to help bridge the gap between guideline recommendations and measurable processes and outcomes. Measurement and subsequent implementation of these metrics could be a central step in the improvement of patient care and outcomes in this high-risk population.

Identifying an Optimal Liver Frailty Index Cutoff to Predict Waitlist Mortality in Liver Transplant Candidates.

BACKGROUND AND AIMS: Frailty, as measured by the Liver Frailty Index (LFI), is associated with liver transplant (LT) waitlist mortality. We sought to identify an optimal LFI cutoff that predicts waitlist mortality. APPROACH AND RESULTS: Adults with cirrhosis awaiting LT without hepatocellular carcinoma at nine LT centers in the United States with LFI assessments were included. Multivariable competing risk analysis assessed the relationship between LFI and waitlist mortality. We identified a single LFI cutoff by evaluating the fit of the competing risk models, searching for the cutoff that gave the best model fit (as judged by the pseudo-log-likelihood). We ascertained the area under the curve (AUC) in an analysis of waitlist mortality to find optimal cutoffs at 3, 6, or 12 months. We used the AUC to compare the discriminative ability of LFI+Model for End Stage Liver Disease-sodium (MELDNa) versus MELDNa alone in 3-month waitlist mortality prediction. Of 1,405 patients, 37 (3%), 82 (6%), and 135 (10%) experienced waitlist mortality at 3, 6, and 12 months, respectively. LFI was predictive of waitlist mortality across a broad LFI range: 3.7-5.2. We identified an optimal LFI cutoff of 4.4 (95% confidence interval [CI], 4.0-4.8) for 3-month mortality, 4.2 (95% CI, 4.1-4.4) for 6-month mortality, and 4.2 (95% CI, 4.1-4.4) for 12-month mortality. The AUC for prediction of 3-month mortality for MELDNa was 0.73; the addition of LFI to MELDNa improved the AUC to 0.79. CONCLUSIONS: LFI is predictive of waitlist mortality across a wide spectrum of LFI values. The optimal LFI cutoff for waitlist mortality was 4.4 at 3 months and 4.2 at 6 and 12 months. The discriminative performance of LFI+MELDNa was greater than MELDNa alone. Our data suggest that incorporating LFI with MELDNa can more accurately represent waitlist mortality in LT candidates.

Disease Knowledge, Health-Related Quality of Life, and Lifestyle Behavior Change in Patients with Nonalcoholic Fatty Liver Disease: Impact of an Educational Intervention.

BACKGROUND: Lifestyle modification is currently the only treatment for nonalcoholic fatty liver disease (NAFLD). The most effective way to motivate behavior change in this population is not well understood. AIMS: The aims of this study were to characterize the association between patient disease knowledge, attitudes, and behaviors and to determine the impact of an educational intervention. METHODS: Adults with NAFLD had the following assessed before and after an educational intervention: (1) disease knowledge; (2) health-related quality of life (HRQOL); (3) physical activity; (4) diet; (5) stages of change; and (6) clinical variables. RESULTS: Median age of the cohort (N = 248) was 53.5, 46% were male, 85% were white, and median body mass index was 33.9. Forty-eight percentage had nonalcoholic steatohepatitis, and 28% had cirrhosis. The median correct knowledge score was 73.6%, median Chronic Liver Disease Questionnaire-NAFLD was 5.2/7, and diet score was 7/16 (higher indicating unhealthy diets). The cohort was sedentary at baseline, with 46% and 60% in active phases of change for nutrition and physical activity, respectively. Fifty-six (22%) had all three high-risk behaviors (sedentary, poor diet scores, low stage of change), which was independently associated with depression. The educational intervention improved diet scores, HRQOL, stages of change, and weight. CONCLUSIONS: Despite good disease knowledge, NAFLD participants were sedentary and 1/4 had high-risk lifestyle behaviors. An educational intervention had positive impacts on clinical outcomes, though effect size was small. Pairing educational interventions with targeted interventions to motivate behavior change can improve care for patients with NAFLD.

Acute Liver Injury in Patients Hospitalized with COVID-19.

INTRODUCTION: The prevalence and significance of acute liver injury in patients with COVID-19 are poorly characterized. METHODS: Patients with confirmed COVID-19 who were hospitalized in geographically diverse medical centers in North America were included. Demographics, symptoms, laboratory data results, and outcomes were recorded. Linear and logistic regression identified factors associated with liver injury, in-hospital mortality, and length of stay (LOS). RESULTS: Among 1555 patients in the cohort, most (74%) had an elevated alanine aminotransferase (ALT) during hospitalization, which was very severe (> 20 × upper limit of normal [ULN]) in 3%. Severe acute liver injury (ALI) was uncommon, occurring in 0.1% on admission and 2% during hospitalization. No patient developed acute liver failure (ALF). Higher ALT was associated with leukocytosis (per mL3) (ß 10.0, 95% confidence interval (CI) 6.7-12.6, p < 0.001) and vasopressors use (ß 80.2, 95%CI 21.5-138.8, p = 0.007). In-hospital mortality was associated with ALT > 20 × ULN (unadjusted OR 6.0, 95%CI 3.1-11.5, p < 0.001), ALP > 3 × ULN (unadjusted OR 4.4, 95%CI 2.5-7.7, p < 0.001), and severe ALI (unadjusted OR 6.8, 95%CI 3.0-15.3, p < 0.001) but lost significance after adjusting for covariates related to severe COVID-19 and hemodynamic instability. Elevated ALP and ALT were associated with longer LOS, admission to intensive care, mechanical ventilation, vasopressor use, and extracorporeal membrane oxygenation use (p < 0.001). CONCLUSIONS: Transaminase elevation is common in hospitalized patients with COVID-19. Severe ALI is rare, and ALF may not be a complication of COVID-19. Extreme elevations in liver enzymes appear to be associated with mortality and longer LOS due to more severe systemic disease rather than SARS-CoV-2-related hepatitis.

Loneliness in adults awaiting liver transplantation at 7 U.S. transplant centers.

INTRODUCTION: Loneliness, "a subjective feeling of being isolated", is a strong predictor of adverse health. We characterized loneliness in patients with end-stage liver disease (ESLD) awaiting liver transplantation (LT). METHODS: We surveyed loneliness in ambulatory ESLD adults awaiting LT at 7 U.S. sites using the validated UCLA Three-Item Loneliness Scale, May2020-Jan2021; "lonely"=total ≥5. Liver Frailty Index (LFI) assessed frailty; "frail"=LFI≥4.4. Logistic regression associated loneliness and co-variables. RESULTS: Of 454 participants, median MELDNa was 14 (IQR 10-19) and 26% met criteria for "lonely". Compared to those not lonely, those lonely were younger (57 v. 61y), more likely to be female (48% v. 31%) or frail (21 v. 11%), and less likely to be working (15% v. 26%) or in a committed partnership (52% v. 71%). After multivariable adjustment, frailty (OR=2.24, 95%CI=1.23-4.08), younger age (OR=1.19, 95%CI=1.07-1.34), female sex (OR=1.83, 95%CI=1.14-2.92), not working (OR=2.16, 95%CI=1.16-4.03), and not in a committed partnership (OR=2.07, 95%CI=1.29-3.32) remained significantly associated with higher odds of loneliness. CONCLUSION: Loneliness is prevalent in adults awaiting LT, and independently associated with younger age, female sex and physical frailty. These data lay the foundation to investigate the extent to which loneliness impacts health outcomes in LT, as in the general population. Clinical Trial Registry Website: https://clinicaltrials.gov Trial Number: NCT03228290.

Digestive Manifestations in Patients Hospitalized With Coronavirus Disease 2019.

BACKGROUND & AIMS: The prevalence and significance of digestive manifestations in coronavirus disease 2019 (COVID-19) remain uncertain. We aimed to assess the prevalence, spectrum, severity, and significance of digestive manifestations in patients hospitalized with COVID-19. METHODS: Consecutive patients hospitalized with COVID-19 were identified across a geographically diverse alliance of medical centers in North America. Data pertaining to baseline characteristics, symptomatology, laboratory assessment, imaging, and endoscopic findings from the time of symptom onset until discharge or death were abstracted manually from electronic health records to characterize the prevalence, spectrum, and severity of digestive manifestations. Regression analyses were performed to evaluate the association between digestive manifestations and severe outcomes related to COVID-19. RESULTS: A total of 1992 patients across 36 centers met eligibility criteria and were included. Overall, 53% of patients experienced at least 1 gastrointestinal symptom at any time during their illness, most commonly diarrhea (34%), nausea (27%), vomiting (16%), and abdominal pain (11%). In 74% of cases, gastrointestinal symptoms were judged to be mild. In total, 35% of patients developed an abnormal alanine aminotransferase or total bilirubin level; these were increased to less than 5 times the upper limit of normal in 77% of cases. After adjusting for potential confounders, the presence of gastrointestinal symptoms at any time (odds ratio, 0.93; 95% CI, 0.76-1.15) or liver test abnormalities on admission (odds ratio, 1.31; 95% CI, 0.80-2.12) were not associated independently with mechanical ventilation or death. CONCLUSIONS: Among patients hospitalized with COVID-19, gastrointestinal symptoms and liver test abnormalities were common, but the majority were mild and their presence was not associated with a more severe clinical course.

Bariatric surgery and the risk of alcohol-related cirrhosis and alcohol misuse.

BACKGROUND & AIMS: Bariatric surgery is common, but alcohol misuse has been reported following these procedures. We aimed to determine if bariatric surgery is associated with increased risk of alcohol-related cirrhosis (AC) and alcohol misuse. METHODS: Retrospective observational analysis of obese adults with employer-sponsored insurance administrative claims from 2008 to 2016. Subjects with diagnosis codes for bariatric surgery were included. Primary outcome was risk of AC. Secondary outcome was risk of alcohol misuse. Bariatric surgery was divided into before 2008 and after 2008 to account for patients who had a procedure during the study period. Cox proportional hazard regression models using age as the time variable were used with interaction analyses for bariatric surgery and gender. RESULTS: A total of 194 130 had surgery from 2008 to 2016 while 209 090 patients had bariatric surgery prior to 2008. Age was 44.1 years, 61% women and enrolment was 3.7 years. A total of 4774 (0.07%) had AC. Overall risk of AC was lower for those who received sleeve gastrectomy and laparoscopic banding during the study period (HR 0.4, P <.001; HR 0.43, P =.02) and alcohol misuse increased for Roux-en-Y and sleeve gastrectomy recipients (HR 1.86 and 1.35, P <.001, respectively). In those who had surgery before 2008, women had increased risk of AC and alcohol misuse compared to women without bariatric surgery (HR 2.1 [95% CI: 1.79-2.41] for AC; HR 1.98 [95% CI 1.93-2.04]). CONCLUSIONS: Bariatric surgery is associated with a short-term decreased risk of AC but potential long-term increased risk of AC in women. Post-operative alcohol surveillance is necessary to reduce this risk.

The relationship between frailty and cirrhosis etiology: From the Functional Assessment in Liver Transplantation (FrAILT) Study.

BACKGROUND & AIMS: Cirrhosis leads to malnutrition and muscle wasting that manifests as frailty, which may be influenced by cirrhosis aetiology. We aimed to characterize the relationship between frailty and cirrhosis aetiology. METHODS: Included were adults with cirrhosis listed for liver transplantation (LT) at 10 US centrer who underwent ambulatory testing with the Liver Frailty Index (LFI; 'frail' = LFI ≥ 4.4). We used logistic regression to associate aetiologies and frailty, and competing risk regression (LT as the competing risk) to determine associations with waitlist mortality (death/delisting for sickness). RESULTS: Of 1,623 patients, rates of frailty differed by aetiology: 22% in chronic hepatitis C, 31% in alcohol-associated liver disease (ALD), 32% in non-alcoholic fatty liver disease (NAFLD), 21% in autoimmune/cholestatic and 31% in 'other' (P < .001). In univariable logistic regression, ALD (OR 1.53, 95% CI 1.12-2.09), NAFLD (OR 1.64, 95% CI 1.18-2.29) and 'other' (OR 1.58, 95% CI 1.06-2.36) were associated with frailty. In multivariable logistic regression, only ALD (OR 1.40; 95% 1.01-1.94) and 'other' (OR 1.59; 95% 1.05-2.40) remained associated with frailty. A total of 281 (17%) patients died/were delisted for sickness. In multivariable competing risk regression, LFI was associated with waitlist mortality (sHR 1.05, 95% CI 1.03-1.06), but aetiology was not (P > .05 for each). No interaction between frailty and aetiology on the association with waitlist mortality was found (P > .05 for each interaction term). CONCLUSIONS: Frailty is more common in patients with ALD, NAFLD and 'other' aetiologies. However, frailty was associated with waitlist mortality independent of cirrhosis aetiology, supporting the applicability of frailty across all cirrhosis aetiologies.

Changes in frailty are associated with waitlist mortality in patients with cirrhosis.

BACKGROUND & AIMS: To date, studies evaluating the association between frailty and mortality in patients with cirrhosis have been limited to assessments of frailty at a single time point. We aimed to evaluate changes in frailty over time and their association with death/delisting in patients too sick for liver transplantation. METHODS: Adults with cirrhosis, listed for liver transplantation at 8 US centers, underwent ambulatory longitudinal frailty testing using the liver frailty index (LFI). We used multilevel linear mixed-effects regression to model and predict changes in LFI (ΔLFI) per 3 months, based on age, gender, model for end-stage liver disease (MELD)-Na, ascites, and hepatic encephalopathy, categorizing patients by frailty trajectories. Competing risk regression evaluated the subhazard ratio (sHR) of baseline LFI and predicted ΔLFI on death/delisting, with transplantation as the competing risk. RESULTS: We analyzed 2,851 visits from 1,093 outpatients with cirrhosis. Patients with severe worsening of frailty had worse baseline LFI and were more likely to have non-alcoholic fatty liver disease, diabetes, or dialysis-dependence. After a median follow-up of 11 months, 223 (20%) of the overall cohort died/were delisted because of sickness. The cumulative incidence of death/delisting increased by worsening ΔLFI group. In competing risk regression adjusted for baseline LFI, age, height, MELD-Na, and albumin, a 0.1 unit change in ΔLFI per 3 months was associated with a 2.04-fold increased risk of death/delisting (95% CI 1.35-3.09). CONCLUSION: Worsening frailty was significantly associated with death/delisting independent of baseline frailty and MELD-Na. Notably, patients who experienced improvements in frailty had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty, using the LFI, in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty. LAY SUMMARY: Frailty, as measured at a single time point, is predictive of death in patients with cirrhosis, but whether changes in frailty over time are associated with death is unknown. In a study of over 1,000 patients with cirrhosis who underwent frailty testing, we demonstrate that worsening frailty is strongly linked with mortality, regardless of baseline frailty and liver disease severity. Notably, patients who experienced improvements in frailty over time had a lower risk of death/delisting. Our data support the longitudinal measurement of frailty in patients with cirrhosis and lay the foundation for interventional work aimed at reversing frailty.

Factors Associated with Survival of Patients With Severe Acute-On-Chronic Liver Failure Before and After Liver Transplantation.

BACKGROUND & AIMS: Liver transplantation for patients with acute-on-chronic liver failure (ACLF) with 3 or more failing organs (ACLF-3) is controversial. We compared liver waitlist mortality or removal according to model for end-stage liver disease (MELD) score vs ACLF category. We also studied factors associated with reduced odds of survival for 1 year after liver transplantation in patients with ACLF-3. METHODS: We analyzed data from the United Network for Organ Sharing (UNOS) from 2005 through 2016. We identified patients who were on the waitlist (100,594) and those who received liver transplants (50,552). Patients with ACLF were identified based on the European Association for the Study of the Liver-chronic liver failure criteria. Outcomes were evaluated with competing risks regression, Kaplan-Meier analysis, and Cox proportional hazards regression. RESULTS: Patients with ACLF-3 were more likely to die or be removed from the waitlist, regardless of MELD-sodium (MELD-Na) score, compared with the other ACLF groups; the proportion was greatest for patients with an ACLF-3 score and MELD-Na score below 25 (43.8% at 28 days). Mechanical ventilation at liver transplantation (hazard ratio [HR] 1.49; 95% confidence interval [CI] 1.22-1.84), donor risk index above 1.7 (HR 1.22; 95% CI 1.09-1.35), and liver transplantation within 30 days of listing (HR 0.89; 95% CI 0.81-0.98) were independently associated with survival for 1 year after liver transplantation CONCLUSIONS: In an analysis of data from the UNOS registry, we found high mortality among patients with ACLF-3 on the liver transplant waitlist, even among those with lower MELD-Na scores. So, certain patients with ACLF-3 have poor outcomes regardless of MELD-Na score. Liver transplantation increases odds of survival for these patients, particularly if performed within 30 days of placement on the waitlist. Mechanical ventilation at liver transplantation and use of marginal organs were associated with increased risk of death.