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Predictors of poor outcome associated with variceal bleeding remain suboptimal. In patients with cirrhosis, serum lactate combined with Model for End-Stage Liver Disease (MELD-LA) improved prediction across heterogeneous populations. However, prognostic properties have not yet been assessed in the context of variceal bleeding.We aimed to evaluate the predictive performance of MELD-LA compared to MELD, lactate, and nadir hemoglobin in cirrhosis patients with variceal bleeding.In this multicenter study, we identified 472 patients with variceal bleeding from a German primary cohort (University Hospitals Hamburg/Frankfurt/Cologne), and two independent external validation cohorts [Veterans Affairs (VA), Baylor University]. Discrimination for 30-day mortality was analyzed and scores were compared. MELD-LA was evaluated separately in validation cohorts to ensure consistency of findings.In contrast to nadir hemoglobin, MELD and peak-lactate at time of bleeding were significantly higher in 30-day non-survivors in the primary cohort (p = 0.708; p 0.001). MELD-LA had excellent discrimination for 30-day mortality (AUROC 0.82, 95% CI 0.76-0.88), better than MELD and peak-lactate (AUROC 0.78, 95% CI 0.71-0.84; AUROC 0.73, 95% CI 0.66-0.81). MELD-LA predicted 30-day mortality independently of age, sex, severity of liver disease and vasopressor support (HR 1.29 per 1-point-increase of MELD-LA; 95% CI 1.19-1.41; p 0.001). Similarly, MELD-LA demonstrated excellent discrimination for 30-day mortality in the VA (AUROC = 0.86, 95% CI 0.79-0.93) and Baylor cohort (AUROC = 0.85, 95% CI 0.74-0.95).MELD-LA significantly improves discrimination of short-term mortality associated with variceal bleeding, compared to MELD, peak-lactate and nadir hemoglobin. Thus, MELD-LA might represent a useful and objective marker for risk assessment and therapeutic intervention in patients with variceal bleeding.

Patients with compensated cirrhosis and chronic kidney disease are increasing along with demand for simultaneous liver kidney transplant (SLKT) and shortages of organs for transplantation. Although these well-compensated patients may not need a liver organ, the alternative of kidney transplant alone (KTA) poses the risk of liver decompensation. Therefore, we aim to characterize outcomes among patients with compensated cirrhosis and chronic kidney disease listed for SLKT or receiving KTA to inform clinical decisions.The 2-part retrospective study included a national cohort of patients listed for SLKT in United Network for Organ Sharing from January 2003 to June 2019 with Child A cirrhosis, with model for end-stage liver disease25, and receiving dialysis; and a cohort of patients who underwent KTA from 2004 to 2019 with Child A cirrhosis identified through a 4-center chart review. Waitlist outcomes (SLKT, death, and clinical improvement) and post-KTA liver decompensation and survival were evaluated in the cohorts, respectively.In the national SLKT cohort (N = 705, median age 56 y, 68.8% male), 5-y cumulative incidence of SLKT was 43.1%, death 32.1%, and clinical improvement 9.1%. Among SLKT recipients, 36.3% remained Child A without ascites or encephalopathy at transplant. In the local KTA cohort (N = 34, median age 54 y, 79.4% male), none had ascites or hepatic encephalopathy before KTA, but 15 had clinical portal hypertension. Five-y post-KTA incidence of liver decompensation was 36.8%, and survival was 89.2%.SLKT may not be necessary for some patients with compensated cirrhosis needing kidney transplant. KTA is safe for selected patients with intact liver biochemical function, even with portal hypertension but without hepatic encephalopathy or ascites.

Hepatic encephalopathy (HE) is a neurocognitive condition in cirrhosis leading to frequent hospitalizations. Nonselective beta-blockers (NSBBs) are the mainstay of pharmacologic treatment in cirrhotic patients. We hypothesized that since NSBBs decrease cardiac output and portal flow, the decreased metabolic filtering process of liver parenchyma may lead to increased HE-related hospitalizations.To evaluate the impact of NSBB administration on HE-related readmissions in cirrhotic patients.In this retrospective cohort study, we included 393 patients admitted to Baylor University Medical Center for liver-related portal hypertension indications between January 2013 and July 2018. Independent predictors of the first HE-related readmissions were identified using Cox proportional hazards analysis. The cumulative incidence of the first HE-related readmissions between patients receiving NSBBs and not receiving NSBBs was examined using Fine-Gray modeling to account for the competing risk of death or liver transplantation.The mean age was 58.1 ± 10.2 years and most patients fell into Child class C (49.1%) or B (43.8%). The median Model for End-Stage Liver Disease-Sodium score was 22 (IQR: 11). The cumulative incidence of the first HE-related readmissions was significantly higher in patients taking NSBBs compared to patients not receiving NSBBs (71.8%NSBB use is independently associated with increased HE-related readmissions in patients with cirrhosis, regardless of liver disease severity.

The burden of liver disease is substantial and increasing; the impact of comorbid chronic diseases on the clinical course of patients with compensated and decompensated cirrhosis is not well-defined. The aim of this study was to examine the individual and additive impact of comorbid chronic diseases on mortality in patients with cirrhosis.In this population-based study, we used Cox proportional hazards modeling with time-dependent covariates to assess the impact of comorbid chronic diseases (diabetes mellitus, chronic kidney disease, and cardiovascular disease [CVD]) on mortality in patients with cirrhosis in a large, diverse Metroplex.There were 35,361 patients with cirrhosis (mean age 59.5 years, 41.8% females, 29.7% non-White, and 17.5% Hispanic ethnicity). Overall, the presence of chronic comorbidities was 1 disease (28.9%), 2 diseases (17.5%), and 3 diseases (12.6%) with a majority having CVD (45%). Adjusted risk of mortality progressively increased with an increase in chronic diseases from 1 (hazard ratio [HR] 2.5, 95% confidence interval [CI] 2.23-2.8) to 2 (HR 3.27.95% CI 2.9-3.69) to 3 (HR 4.52, 95% CI 3.99-5.12) diseases. Survival of patients with compensated cirrhosis and 3 chronic diseases was similar to subsets of decompensated cirrhosis (67.7% as compared with decompensated cirrhosis with 1-3 conditions, 61.9%-63.9%).In patients with cirrhosis, a focus on comorbid chronic disease(s) as potential management targets may help avoid premature mortality, regardless of etiology. Multidisciplinary care early in the clinical course of cirrhosis is needed in addition to the current focus on management of complications of portal hypertension.

The role of noninvasive liver disease assessment by two-dimensional shear wave elastography (2D-SWE) to diagnose fibrosis is well described in patients with chronic liver disease. However, its role in prognosis, especially after liver transplantation (LT) has not been adequately examined. We hypothesized that elevated liver stiffness measurement (LSM) as measured by 2D-SWE after LT predicts future morbidity and mortality independent of fibrosis by liver biopsy. In a prospective cohort study, consecutive LT recipients underwent concomitant protocol 2D-SWE and protocol liver biopsy (2012-2014), with the assessor blinded to biopsy findings. We examined the baseline correlation of LSM with fibrosis stage and the association between elevated LSM and the development of subsequent clinical outcomes and all-cause mortality. A total of 187 LT recipients (median age 58 years, 38.5% women, median body mass index 26.5 kg/m

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.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.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.

Background and aims The burden of hepatocellular carcinoma (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 along the HCC care continuum. Approach and results 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 patient-reported outcomes (PRO) 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. Conclusions 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.

Estimated glomerular filtration rate (eGFR) is adjusted for Black race in commonly used formulas. This has potential implications for access to simultaneous liver-kidney transplantation (SLKT) as qualifying criteria rely on eGFR. We performed a retrospective study of United Network for Organ Sharing national transplant registry data between February 28, 2002, and March 31, 2019, to evaluate the proportion of Black patients who would be reclassified as meeting SLKT criteria (as defined per current policies) if race adjustment were removed from 2 prominent eGFR equations (Modification of Diet in Renal Disease-4 [MDRD-4] and Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]). Of the 7937 Black patients listed for transplant during the study period, we found that 3.6% would have been reclassified as qualifying for chronic kidney disease (CKD)-related SLKT with removal of race adjustment for MDRD-4, and 3.0% would have been reclassified with CKD-EPI; this represented 23.7% and 18.7% increases in SLKT candidacy, respectively. Reclassification impacted women more than men (eg, 4.5% versus 3.0% by MDRD-4; P

Objective To estimate the prevalence, risk factors, and consequences of cost-related medication nonadherence (CRN) in individuals with chronic liver diseases (CLDs) in the United States. Patients and Methods Using the National Health Interview Survey from January 1, 2014, to December 31, 2018, we identified individuals with CLDs. Using complex weighted survey analysis, we obtained national estimates and risk factors for CRN and its association with cost-reducing behaviors and measures of financial toxicity. We evaluated the association of CRN with unplanned health care use, adjusting for age, sex, race/ethnicity, insurance, income, education, and comorbid conditions. Results Of 3237 respondents (representing 4.6 million) US adults with CLDs, 813 (representing 1.2 million adults, or 25%; 95% CI, 23% to 27%) reported CRN, of whom 68% (n=554/813) reported maladaptive cost-reducing behaviors. Younger age, female sex, low income, and multimorbidity were associated with a higher prevalence of CRN. Compared with patients without CRN, patients experiencing CRN had 5.1 times higher odds of financial hardship from medical bills (adjusted odds ratio [aOR], 5.05; 95% CI, 3.73 to 6.83) and 2.9 times higher odds of food insecurity (aOR, 2.85; 95% CI, 2.02 to 4.01). The CRN was also associated with 1.5 times higher odds of emergency department visits (aOR, 1.46; 95% CI, 1.11 to 1.94). Conclusion We observed a high prevalence of CRN and associated consequences such as high financial distress, financial hardship from medical bills, food insecurity, engagement in maladaptive cost-reducing strategies, increased health care use, and work absenteeism among patients with CLD. These financial determinants of health have important implications in the context of value-based care.

The COVID-19 pandemic has been associated with a change in alcohol consumption, resulting in an increase in alcohol-related liver disease. In this study, we reviewed the literature on (acute) alcohol-associated hepatitis (AH) in the context of the COVID-19 pandemic.PubMed, Ovid MEDLINE, Embase, Cochrane Library, and the pre-print servers medRxiv and bioRxiv were searched to retrieve 320 articles of which 15 abstracts, 7 full-text articles, 4 letters, 1 case report, and 1 poster were included for the final structured review.The pandemic resulted in an increase in healthcare utilization related to alcohol consumption. Admissions related to AH increased by 50% (range: 11-100%) during this time, which was disproportionally high in women, younger adults, African Americans, Hispanics, and patients living in rural areas. During this period, the number of new waiting list registrations and candidates with AH receiving liver transplantation (LT) simultaneously increased, which highlights the need for an approach to providing improvised healthcare services at the regional and individual levels.

Texas has the highest age-adjusted incidence rate of hepatocellular carcinoma (HCC) in the United States. To address cancer prevention and early detection through research, Cancer Prevention and Research Institute of Texas (CPRIT) has funded the Texas Collaborative Center for Hepatocellular Cancer (TeCH) to facilitate liver cancer research, education and advocacy activities. This paper describes the organizational structure, program measures, the actions completed and future plans of TeCH. This center is comprised of several cores and committees including the Administrative Core, Steering Committee, Data and Biospecimen Core, Scientific Committee, Clinical Network Committee, and the Community Outreach Committee. Each core and committee provide its own level of connectivity and necessary research support. We have developed and published a TeCH Framework, a conceptual model designed for improving primary and secondary prevention of HCC. TeCH and its committees facilitate connections and collaborations among HCC researchers and clinicians, healthcare leaders, biotechnology companies and the public to reduce liver cancer mortality in Texas by 2030.

Cirrhosis is a heterogeneous disease that cannot be studied as a single entity and is classified in two main prognostic stages: compensated and decompensated cirrhosis. Portal hypertension, characterized by a pathological increase of the portal pressure and by the formation of portal-systemic collaterals that bypass the liver, is the initial and main consequence of cirrhosis and is responsible for the majority of its complications. A myriad of treatment options exists for appropriately managing the most common complications of portal hypertension, including acute variceal bleeding and refractory ascites. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Summary: Background: Survival of liver transplant recipients beyond 1 year since transplantation is compromised by an increased risk of cancer, cardiovascular events, infection, and graft failure. Few clinical tools are available to identify patients at risk of these complications, which would flag them for screening tests and potentially life-saving interventions. In this retrospective analysis, we aimed to assess the ability of deep learning algorithms of longitudinal data from two prospective cohorts to predict complications resulting in death after liver transplantation over multiple timeframes, compared with logistic regression models. Methods: In this machine learning analysis, model development was done on a set of 42 146 liver transplant recipients (mean age 48·6 years [SD 17·3]; 17 196 [40·8%] women) from the Scientific Registry of Transplant Recipients (SRTR) in the USA. Transferability of the model was further evaluated by fine-tuning on a dataset from the University Health Network (UHN) in Canada (n=3269; mean age 52·5 years [11·1]; 1079 [33·0%] women). The primary outcome was cause of death, as recorded in the databases, due to cardiovascular causes, infection, graft failure, or cancer, within 1 year and 5 years of each follow-up examination after transplantation. We compared the performance of four deep learning models against logistic regression, assessing performance using the area under the receiver operating characteristic curve (AUROC). Findings: In both datasets, deep learning models outperformed logistic regression, with the Transformer model achieving the highest AUROCs in both datasets (p

Accurate assessment of donor quality at the time of organ offer for liver transplantation candidates may be inadequately captured by the donor risk index (DRI). We sought to develop and validate a novel objective and simple model to assess donor risk using donor level variables available at the time of organ offer. We utilized national data from candidates undergoing primary LT (2013-2019) and assessed the prediction of graft failure 1 year after LT. The final components were donor Insulin-dependent diabetes mellitus, Donor type (DCD or DBD), cause of Death = CVA, serum creatinine, Age, height, and weight (length). The ID

The volume of abdominal organ offers received by the Baylor Simmons Transplant Institute has increased over time, resulting in a higher workload for our donor call team. To quantify the increase in organ offers, determine the characteristics of these offers, and estimate the impact on our transplant center workload, we collected center-specific organ offer data from May 2019 to July 2021 using the UNOS Center Acceptance and Refusal Evaluation Report and performed a time study that collected the number of communications and time spent on communications for organ offers made during a typical week. The total offers per month increased by 140% (270/month to 648/month), while the number of transplanted organs remained stable. In addition, the percentage of offers for organs that were never transplanted increased from 54% to 75%. In a representative week-long time study, surgeons made 505, center coordinators 590, and answering service coordinators 318 distinct communications, averaging 3, 4, and 2 communications/hour. Between November 2019 and July 2021, offer-related workload increased by an estimated 97%. These results demonstrate a sizeable inefficiency in abdominal organ allocation associated with a nonrecoverable cost to our transplant center.

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.

While previous research has compared outcomes between living donor liver transplantation (LDLT) and deceased donor liver transplantation, evidence is lacking regarding how donation after circulatory death (DCD) vs donation after brain death (DBD) affects this comparison. Using data from the Scientific Registry of Transplant Recipients for adults listed for liver transplant from 2012 to 2018, we compared 5-year patient and graft survival, readmissions, posttransplant chronic kidney disease (CKD), and return to work for 25,151 patients who underwent LDLT (1223 [4.9%]), DCD-LT (1431 [6.4%]), and DBD-LT (22,497 [89.4%]). LDLT recipients were significantly more likely to have a Model for End-Stage Liver Disease (MELD) score < 15 and to be working prior to transplant (P < 0.001 for both). At 5 years posttransplant, LDLT recipients had significantly more readmissions, but significantly less CKD and better survival than DBD-LT and DCD-LT recipients, as well as significantly better graft survival than DCD-LT recipients (P ≤ 0.01 for all). Significantly more LDLT recipients also returned to work for income (P < 0.01). This study shows a clear advantage of LDLT vs DCD-LT. This information should be weighed in transplantation decisions for patients such as those with low MELD scores who will realistically only be considered for DCD-LT.

BACKGROUND: Accuracy of glomerular filtration rate estimating (eGFR) equations has significant implications in cirrhosis, potentially guiding simultaneous liver kidney allocation and drug dosing. Most equations adjust for Black race, partially accounted for by reported differences in muscle mass by race. Patients with cirrhosis, however, are prone to sarcopenia which may mitigate such differences. We evaluated the association between baseline eGFR and incident acute kidney injury (AKI) in patients with cirrhosis with and without race adjustment. METHODS: We conducted a retrospective national cohort study of veterans with cirrhosis. Baseline eGFR was calculated using multiple eGFR equations including Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), both with and without race adjustment. Poisson regression was used to investigate the association between baseline eGFR and incident AKI events per International Club of Ascites criteria. RESULTS: We identified 72,267 patients with cirrhosis, who were 97.3% male, 57.8% white, and 19.7% Black. Over median follow-up 2.78 years (interquartile range 1.22-5.16), lower baseline eGFR by CKD-EPI was significantly associated with higher rates of AKI in adjusted models. For all equations this association was minimally impacted when race adjustment was removed. For example, removal of race adjustment from CKD-EPI resulted in a 0.1% increase in the association between lower eGFR and higher rate of AKI events per 15mL/min/1.73m(2) change (p

Background Polygenic risk scores (PRS) hold the promise to refine prognostication in hepatocellular cancer (HCC). The few available HCC PRS include germline risk variants identified among individuals of mostly European ancestry, but data are lacking on the transportability of these PRS in multiethnic U.S patients with cirrhosis from multiple etiologies. Methods We used data from 1644 patients with cirrhosis enrolled in two prospective cohort studies in the U.S. Patients were followed until HCC diagnosis, death, liver transplantation, or last study visit through June 30, 2021. The high-risk variants in PNPLA3-MBOAT7-TM6SF2-GCKR were combined in a PRS and we evaluated its association with HCC. Discriminatory accuracy was assessed using the C-statistic. Results During 4,759 person-years of follow-up, 93 patients developed HCC. Mean age was 59.8 years, 68.6% were male, 27.2% Hispanic, 25.1% non-Hispanic Black, 25.7% had NAFLD, 42.1% had heavy alcohol use, and 19.5% had active HCV. HCC risk increased by 134% per unit increase in PRS (HR = 2.30; 95% CI, 1.35–3.92). Compared to cirrhosis patients in the lowest tertile of the PRS, those in the highest tertile had 2-fold higher risk of HCC (HR = 2.05; 95% CI, 1.22–3.44). The PRS alone had modest discriminatory ability (C-statistic = 0.58; 95% CI, 0.52–0.63); however, adding PRS to a predictive model with traditional HCC risk factors had a C-statistic of 0.70 (95% CI, 0.64–0.76), increasing from 0.68 without the PRS (p = 0.0012). Conclusions Our findings suggest that PRS may enhance risk prediction for HCC in contemporary U.S. cirrhosis patients.

The burden of cirrhosis hospitalizations is increasing. The admission Model for End-Stage Liver Disease-lactate (MELD-lactate) was recently demonstrated to be a superior predictor of in-hospital mortality compared with MELD in limited cohorts. We identified specific classes of hospitalizations where MELD-lactate may be especially useful and evaluated the predictive role of lactate clearance. This was a retrospective cohort study of 1036 cirrhosis hospitalizations for gastrointestinal bleeding, infection, or other portal hypertension-related indications in the Veterans Health Administration where MELD-lactate was measured on admission. Performance characteristics for in-hospital mortality were compared between MELD-lactate and MELD/MELD-sodium (MELD-Na), with stratified analyses of MELD categories (≤15, >15 to

BACKGROUND AND AIMS Compared to other chronic diseases, patients with chronic liver disease (CLD) have significantly higher inpatient mortality; accurate models to predict inpatient mortality are lacking. Serum lactate (LA) may be elevated in patients with CLD due to both tissue hypoperfusion as well as decreased LA clearance. We hypothesized that a parsimonious model consisting of Model for End-Stage Liver Disease (MELD) and LA at admission may predict inpatient mortality in patients with CLD. APPROACH AND RESULTS We examined all patients with CLD in two large and diverse health care systems in Texas (North Texas [NTX] and Central Texas [CTX]) between 2010 and 2015. We developed (n = 3,588) and validated (n = 1,804) a model containing MELD and LA measured at the time of hospitalization. We further validated the model in a second cohort of 14 tertiary care hepatology centers that prospectively enrolled nonelective hospitalized patients with cirrhosis (n = 726). MELD-LA was an excellent predictor of inpatient mortality in development (concordance statistic [C-statistic] = 0.81, 95% confidence interval [CI] 0.79-0.82) and both validation cohorts (CTX cohort, C-statistic = 0.85, 95% CI 0.78-0.87; multicenter cohort C-statistic = 0.82, 95% CI 0.74-0.88). MELD-LA performed especially well in patients with specific cirrhosis diagnoses (C-statistic = 0.84, 95% CI 0.81-0.86) or sepsis (C-statistic = 0.80, 95% CI 0.78-0.82). For MELD score 25, inpatient mortality rates were 11.2% (LA = 1 mmol/L), 19.4% (LA = 3 mmol/L), 34.3% (LA = 5 mmol/L), and >50% (LA > 8 mmol/L). A linear increase (P

Etiological risk factors for cirrhosis have changed in the last decade. It remains unclear to what extent these trends in cirrhosis risk factors have changed HCC risk.We used data from two contemporary, prospective multiethnic cohorts of patients with cirrhosis: the Texas Hepatocellular Carcinoma Consortium Cohort and the Houston Veterans Administration Cirrhosis Surveillance Cohort. Patients with cirrhosis were enrolled from seven US centers and followed until HCC diagnosis, transplant, death, or June 30, 2021. We calculated the annual incidence rates for HCC and examined the effects of etiology, demographic, clinical, and lifestyle factors on the risk of HCC. We included 2733 patients with cirrhosis (mean age 60.1 years, 31.3% women). At enrollment, 19.0% had active HCV, 23.3% had cured HCV, 16.1% had alcoholic liver disease, and 30.1% had NAFLD. During 7406 person-years of follow-up, 135 patients developed HCC at an annual incidence rate of 1.82% (95% CI, 1.51-2.13). The annual HCC incidence rate was 1.71% in patients with cured HCV, 1.32% in patients with alcoholic liver disease, and 1.24% in patients with NAFLD cirrhosis. Compared to patients with NAFLD, the risk of progression to HCC was 2-fold higher in patients with cured HCV (HR, 2.04; 95% CI, 1.24-3.35). Current smoking (HR, 1.63; 95% CI, 1.01-2.63) and overweight/obesity (HR, 1.79; 95% CI, 1.08-2.95) were also associated with HCC risk.HCC incidence among patients with cirrhosis was lower than previously reported. HCC risk was variable across etiologies, with higher risk in patients with HCV cirrhosis and lower risk in those with NAFLD cirrhosis. Current smoking and overweight/obesity increased HCC risk across etiologies.

Noninvasive biomarker profiles of acute rejection (AR) could affect the management of liver transplant (LT) recipients. Peripheral blood was collected following LT for discovery (Northwestern University [NU]) and validation (National Institute of Allergy and Infectious Diseases Clinical Trials in Organ Transplantation [CTOT]‐14 study). Blood gene profiling was paired with biopsies showing AR or ADNR (acute dysfunction no rejection) as well as stable graft function samples (Transplant eXcellent—TX). CTOT‐14 subjects had serial collections prior to AR, ADNR, TX, and after AR treatment. NU cohort gene expression (46 AR, 45 TX) was analyzed using random forest models to generate a classifier training set (36 gene probe) distinguishing AR vs TX (area under the curve 0.92). The algorithm and threshold were locked and tested on the CTOT‐14 validation cohort (14 AR, 50 TX), yielding an accuracy of 0.77, sensitivity 0.57, specificity 0.82, positive predictive value (PPV) 0.47, and negative predictive value (NPV) 0.87 for AR vs TX. The probability score line slopes were positive preceding AR, and negative preceding TX and non‐AR (TX + ADNR) (P ≤ .001) and following AR treatment. In conclusion, we have developed a blood biomarker diagnostic for AR that can be detected prior to AR‐associated graft injury as well a normal graft function (non‐AR). Further studies are needed to evaluate its utility in precision‐guided immunosuppression optimization following LT., This study reports on a novel peripheral blood gene signature intended to distinguish acute rejection from other causes and healthy graft function in liver transplant recipients and provide early detection to inform and enhance immunosuppression management.

Background and aims Among patients with cirrhosis awaiting liver transplantation, prediction of wait-list (WL) mortality is adjudicated by the Model for End Stage Liver Disease-Sodium (MELD-Na) score. Replacing serum creatinine (SCr) with estimated glomerular filtration rate (eGFR) in the MELD-Na score may improve prediction of WL mortality, especially for women and highest disease severity. Approach and results We developed (2014) and validated (2015) a model incorporating eGFR using national data (n = 17,095) to predict WL mortality. Glomerular filtration rate (GFR) was estimated using the GFR assessment in liver disease (GRAIL) developed among patients with cirrhosis. Multivariate Cox proportional hazard analysis models were used to compare the predicted 90-day WL mortality between MELD-GRAIL-Na (re-estimated bilirubin, international normalized ratio [INR], sodium, and GRAIL) versus MELD-Na. Within 3 months, 27.8% were transplanted, 4.3% died on the WL, and 4.7% were delisted for other reasons. GFR as estimated by GRAIL (hazard ratio [HR] 0.382, 95% confidence interval [CI] 0.344-0.424) and the re-estimated model MELD-GRAIL-Na (HR 1.212, 95% CI 1.199-1.224) were significant predictors of mortality or being delisted on the WL within 3 months. MELD-GRAIL-Na was a better predictor of observed mortality at highest deciles of disease severity (≥ 27-40). For a score of 32 or higher (observed mortality 0.68), predicted mortality was 0.67 (MELD-GRAIL-Na) and 0.51 (MELD-Na). For women, a score of 32 or higher (observed mortality 0.67), the predicted mortality was 0.69 (MELD-GRAIL-Na) and 0.55 (MELD-Na). In 2015, use of MELD-GRAIL-Na as compared with MELD-Na resulted in reclassification of 16.7% (n = 672) of patients on the WL. Conclusion Incorporation of eGFR likely captures true GFR better than SCr, especially among women. Incorporation of MELD-GRAIL-Na instead of MELD-Na may affect outcomes for 12%-17% awaiting transplant and affect organ allocation.

Liver transplantation (LT) for alcohol associated hepatitis (AH) remains controversial. We convened a consensus conference to examine various aspects of LT for AH. The goal was not to unequivocally endorse LT for AH; instead, it was to propose recommendations for programs that perform or plan to perform LT for AH. Criteria were established to determine candidacy for LT in the setting of AH and included the following: (1) AH patients presenting for the first time with decompensated liver disease that are nonresponders to medical therapy without severe medical or psychiatric comorbidities; (2) a fixed period of abstinence prior to transplantation is not required; and (3) assessment with a multidisciplinary psychosocial team, including a social worker and an addiction specialist/mental health professional with addiction and transplantation expertise. Supporting factors included lack of repeated unsuccessful attempts at addiction rehabilitation, lack of other substance use/dependency, acceptance of diagnosis/insight with a commitment of the patient/family to sobriety, and formalized agreement to adhere to total alcohol abstinence and counseling. LT should be avoided in AH patients who are likely to spontaneously recover. Short-term and longterm survival comparable to other indications for LT must be achieved. There should not be further disparity in LT either by indication, geography, or other sociodemographic factors. Treatment of alcohol-use disorders should be incorporated into pre- and post-LT care. The restrictive and focused evaluation process described in the initial LT experience for AH worldwide may not endure as this indication gains wider acceptance at more LT programs. Transparency in the selection process is crucial and requires the collection of objective data to assess outcomes and minimize center variation in listing. Oversight of program adherence is important to harmonize listing practices and outcomes.

BACKGROUND Alcohol abuse and liver disease are associated with high rates of 30-day hospital readmission, but factors linking alcoholic hepatitis (AH) to readmission are not well understood. We aimed to determine the incidence rate of 30-day readmission for patients with AH and to evaluate potential predictors of readmission. METHODS We used the Nationwide Readmissions Database to determine the 30-day readmission rate for recurrent AH between 2010 and 2014 and examined trends in readmissions during the study period. We also identified the 20 most frequent reasons for readmission. Multivariate survey logistic regression analysis was used to identify factors associated with 30-day readmission. RESULTS Of the 61,750 index admissions for AH, 23.9% were readmitted within 30-days. The rate of readmission did not change significantly during the study period. AH, alcoholic cirrhosis, and hepatic encephalopathy were the most frequent reasons for readmission. In multivariate analysis female sex, leaving against medical advice, higher Charlson comorbidity index, ascites, and history of bariatric surgery were associated with earlier readmissions, whereas older age, payer type (private or self-pay/other), and discharge to skilled nursing-facility reduced this risk. CONCLUSIONS The 30-day readmission rate in patients with AH was high and stable during the study period. Factors associated with readmission may be helpful for development of consensus-based expert guidelines, treatment algorithms, and policy changes to help decrease readmission in AH.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are important drivers of morbidity and mortality in patients with cirrhosis before and after liver transplantation (LT). In this review, we examine the role of novel kidney biomarkers for early recognition of kidney injury. Studies are limited by lack of reference standards, heterogeneous definitions of outcomes and biomarker cutoffs, and inconsistent diagnostic performance. Overall, a change in biomarker is more relevant than an absolute cutoff. Cystatin C and urinary neutrophil gelatinase-associated lipocalin (uNGAL) are the most studied candidate biomarkers and identify AKI or progression of AKI earlier than serum creatinine (sCr). Kidney injury molecule 1 and liver-type fatty acid-binding protein (L-FABP) also show potential. NGAL and interleukin 18 may play a role in differentiating acute tubular necrosis from other forms of AKI. Combining novel biomarkers with the Model for End-Stage Liver Disease score may assist prognosis. Persistent elevations in select markers (eg, NGAL) can portend irreversible injury. Several pretransplantation markers (including sCr) predict posttransplantation kidney dysfunction. Pretransplantation assessment of clinical factors (eg, age, diabetes) and novel markers (osteopontin and tissue inhibitor of metalloproteinases 1 [TIMP-1]) may predict renal kidney recovery after LT. Intraoperative changes in biomarkers predict early post-LT AKI. Prediction of CKD remains difficult, although a combination of biomarkers (eg, beta-2 microglobulin, CD40) is promising. Novel biomarkers have yet to replace sCr in guideline-based evaluation and management of kidney dysfunction in patients with cirrhosis. We propose a theoretical framework for practical incorporation of these biomarkers that considers patient characteristics (risk for irreversible injury), markers of functional and structural change, and assessment of the AKI-CKD continuum to identify patients at the highest risk for progressive kidney disease before and after LT.

BACKGROUND Data are sparse on etiology specific outcomes on waitlist (WL) and post-transplant outcomes among patients with acute on chronic liver failure (ACLF). METHODS AND RESULTS In a retrospective cohort of 14,774 adults from United network for organ sharing (UNOS) database listed for Liver transplantation (LT) with cirrhosis and ACLF (January 2013-June 2019), 40% were due to alcohol-associated liver disease (ALD), followed by hepatitis C virus (HCV) at 20%, non-alcoholic steatohepatitis (19%), cryptogenic cirrhosis (7%), autoimmune hepatitis (5%), primary sclerosing cholangitis (PSC) at 3%, and 2% each for hepatitis B, primary biliary cholangitis (PBC), and metabolic etiology. Using competing risk analysis, cumulative risk of WL mortality was highest for PBC at 20.5% and lowest for PSC at 13.3%, P

Background Knowledge of metabolic processes affected by major hepatectomy (MHx), and the metabolic pathways involved in liver regeneration and recovery of function, is limited and mainly derived from animal models. Assessment of restoration of hepatic function is essential in human living liver donors (LD). Methods We used a targeted metabolomic approach to longitudinally quantify changes in plasma and urine biomarkers from healthy LD. The biomarkers were analyzed before MHx and at scheduled intervals up to 12 months thereafter. Results Marked changes were found in the concentration of 15 primary and secondary plasma bile acids. Most significant changes occurred 2 days after MHx and persisted for up to 3 months. In addition, there were significant changes in acylcarnitine, phospholipid, and amino acid metabolism. The sum of aromatic amino acids and the Fischer ratio, both metabolic markers of liver damage, and the symmetrically demethylated arginine to arginine ratio, a marker of kidney function, were affected. Conclusions This is the first comprehensive longitudinal study investigating metabolic processes during recovery of liver function after MHx in LD. It provides further evidence of full restoration of metabolic processes 3 months after MHx and supports future investigation to understand how metabolic changes affect donors' hepatic function. This article is protected by copyright. All rights reserved.

Background In acute decompensated heart failure (ADHF), noninvasive markers that predict morbidity and mortality are limited. Liver stiffness measurement (LSM) increases with hepatic fibrosis; however it may be falsely elevated in patients with ADHF in the absence of liver disease. We investigated whether elevated LSM predicts cardiac outcomes in ADHF. Methods In a prospective study, we examined 52 ADHF patients without liver disease between 2016 and 2017. Patients underwent liver 2D shear wave elastography (SWE) and were followed for 12 months to assess the outcomes of left ventricular assist device (LVAD), heart transplant (HT) or death. Results The median LSM was elevated in patients who received an LVAD or HT within 30-days compared to those who did not (median [IQR]: 55.6 [22.5 - 63.4] vs 13.8 [9.5 - 40.3] kPa, p = 0.049). Moreover, the risk of composite outcome was highest in the 3rd tertile (>39.8 kPa compared to 1st and 2nd combined, HR 2.83, 95% CI 1.20- 6.67, p = 0.02). Each 1-kPa increase in LSM was associated with a 1%-increase in the incidence rate of readmissions (IRR 1.01, 95% CI 1.00-1.02, p = 0.01). Conclusions LSM may serve as a novel noninvasive tool to determine LVAD, HT or death in patients with ADHF. This article is protected by copyright. All rights reserved.

Post-transplant diabetes mellitus (PTDM) is a complication which reduces allograft and recipient life-span. Polygenic risk scores (PRS) robustly show association with greater type 2 diabetes (T2D) development risk. We examined T2D-PRS in transplant recipients and donors using genome-wide genotyping in 1581 liver recipients, and 1555 donors and 2062 kidney recipients and 533 donors from four centers. Liver and kidney recipient T2D-PRS was associated with pre-transplant T2D and PTDM development. Liver donor, but not kidney donor, T2D-PRS was an independent risk factor for PTDM development. Inclusion of a combined liver recipient and donor T2D-PRS significantly improved PTDM prediction vs clinical characteristics-only models: AUC (95%CI): 67.6% (64.1% − 71.1%) vs. 62.3% (58.8% − 65.8%), p = 0.0001. Liver recipients in the highest quintile of recipient-donor combined T2D-PRS had the greatest PTDM risk: OR (95%CI) = 3.22 (2.07–5.00), p = 1.92E-07, compared to the lowest quintile. T2D-PRS allows identification of transplant candidates with high PTDM risk, for whom early preemptive diabetes management is warranted. Pre-transplant knowledge of donor T2D-PRS in the setting of living liver donation should optimized selection of donors to reduce PTDM.

Post-transplant diabetes mellitus (PTDM) reduces allograft and recipient life span. Polygenic risk scores (PRSs) show robust association with greater risk of developing type 2 diabetes (T2D). We examined the association of PTDM with T2D PRS in liver recipients (n = 1,581) and their donors (n = 1,555), and kidney recipients (n = 2,062) and their donors (n = 533). Recipient T2D PRS was associated with pre-transplant T2D and the development of PTDM. T2D PRS in liver donors, but not in kidney donors, was an independent risk factor for PTDM development. The inclusion of a combined liver donor and recipient T2D PRS significantly improved PTDM prediction compared with a model that included only clinical characteristics: the area under the curve (AUC) was 67.6% (95% confidence interval (CI) 64.1-71.1%) for the combined T2D PRS versus 62.3% (95% CI 58.8-65.8%) for the clinical characteristics model (P = 0.0001). Liver recipients in the highest quintile of combined donor and recipient T2D PRS had the greatest risk of PTDM, with an odds ratio of 3.22 (95% CI 2.07-5.00) (P = 1.92 × 10