Age added to MELD or ACLF predicts survival in patients with alcohol-associated hepatitis declined for liver transplantation.

BACKGROUND: Severe alcohol-associated hepatitis (AH) that is nonresponsive to corticosteroids is associated with high mortality, particularly with concomitant acute-on-chronic liver failure (ACLF). Most patients will not be candidates for liver transplantation (LT) and their outcomes are largely unknown. Our aim was to determine the outcomes of these declined candidates and to derive practical prediction models for transplant-free survival applicable at the time of the waitlist decision. METHODS: We analyzed a database of patients with severe AH who were hospitalized at a LT center from January 2012 to July 2021, using the National Death Index for those lacking follow-up. Clinical variables were analyzed based on the endpoints of mortality at 30, 60, 90, and 180 days. Logistic and Cox regression analyses were used for model derivation. RESULTS: Over 9.5 years, 206 patients with severe AH were declined for LT, mostly for unfavorable psychosocial profiles, with a mean MELD of 33 (±8), and 61% with ACLF. Over a median follow-up of 521 (17.5-1368) days, 58% (119/206) died at a median of 21 (9-124) days. Of 32 variables, only age added prognostic value to MELD and ACLF grade. CLIF-C ACLF score and 2 new models, MELD-Age and ACLF-Age, had similar predictability (AUROC: 0.73, 0.73, 0.72, respectively), outperforming Lille and Maddrey's (AUROC: 0.63, 0.62). In internal cross-validation, the average AUROC was 0.74. ACLF grade ≥2, MELD score >35, and age >45 years were useful cutoffs for predicting increased 90-day mortality from waitlist decision. Only two patients initially declined for LT for AH subsequently underwent LT (1%). CONCLUSIONS: Patients with severe AH declined for LT have high short-term mortality and rare rates of subsequent LT. Age added to MELD or ACLF grade enhances survival prediction at the time of waitlist decision in patients with severe AH declined for LT.

The Survival Benefit of Reabstinence After Harmful Alcohol Use Following Early Liver Transplant for Severe Alcohol-Associated Hepatitis: A Multicenter ACCELERATE Study.

INTRODUCTION: Early (i.e., without mandated period of abstinence) liver transplant (LT) for alcohol-associated hepatitis is the fastest-growing indication for LT in the United States and Europe. Harmful alcohol use after LT is associated with poor outcomes, but the distinction of establishing abstinence after return to drinking (i.e., reabstinence) is understudied. This study aims to characterize the survival outcomes of achieving reabstinence after post-LT harmful alcohol use. METHODS: We analyzed early LT recipients from 12 US LT centers between 2006 and 2021. Post-LT alcohol use was characterized as harmful using criteria of "binge" (≥5 [men] or ≥4 [women] drinks in < 24 hours) or "frequent" (≥4 days in one week) by interview or phosphatidylethanol >20 ng/mL. Reabstinence was defined as ≥12 consecutive months without harmful alcohol use after harmful alcohol use. RESULTS: Among 347 LT recipients (64% male, median age 43, median Model for End-Stage Liver Disease-Sodium score 38) with median post-LT follow-up of 2.2 years (interquartile interval 1.1-3.6), 276 (80%) recipients had no evidence of harmful alcohol use, 35 (10%) recipients had reabstinence, and 36 (10%) recipients had continued harmful alcohol use without reabstinence. Five-year predicted survival, adjusted for age, sex, and Model for End-Stage Liver Disease-Sodium score, was lowest among LT recipients with continued harmful alcohol use (77%), but similar among those with no harmful use (93%) and reabstinence (94%). DISCUSSION: Achieving reabstinence after post-LT harmful alcohol use is associated with similar 5-year post-LT survival compared with those without evidence of post-LT harmful alcohol use. Our findings highlight the importance of early detection and treatment of post-LT alcohol use.

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.

Outcomes after kidney transplant alone in patients with cirrhosis-A case-control study.

BACKGROUND: Guidelines recommend kidney transplant alone (KTA) in compensated cirrhosis based on a few small studies, but this is not widely performed despite its potential benefit to patients and the organ supply. Our aim was to determine the outcomes of KTA in patients with compensated cirrhosis. STUDY DESIGN: From 1/2012 to 12/2021, outcomes in KTA recipients with compensated cirrhosis were retrospectively compared to patients with chronic liver disease (CLD) but no cirrhosis. Patients with compensated cirrhosis were also compared to a matched cohort (based on age, time on hemodialysis, sex, and ethnicity) of KTA recipients without CLD. The outcomes included patient survival, allograft failure, allograft rejection, serious infection, liver decompensation, and length of stay (LOS). RESULTS: Over 9 years, 1562 KTAs were performed, with 150 (9.6%) patients having CLD mostly due to chronic hepatitis C, and a median follow-up of 3.5 years. 32/150 (21%) had compensated cirrhosis at the time of KTA with a mean MELD-Na of 22 (1.5). Matched controls (n = 189) were identified. We found no differences in patient survival (p = .07), allograft failure (p = .6), allograft rejection (p = .43), rates of serious infection (p = .31), as well as LOS (p = .61) among patients with compensated cirrhosis compared to patients with CLD but no cirrhosis, but with higher rates of liver decompensation (p = .004). Similarly, compared to patients without CLD, patients with cirrhosis had similar rates of patient survival (p = .20), allograft failure (p = .27), allograft rejection (p = .62) and LOS (p = .19) but with higher rates of serious infections (p = .001). CONCLUSIONS: Our study supports the safety and efficacy of KTA in patients with compensated cirrhosis.

Transplant selection simulation: Liver transplantation for alcohol-associated hepatitis.

Liver transplantation (LT) for alcohol-associated hepatitis (AH) remains controversial due to concerns about candidate selection subjectivity, post-LT alcohol relapse, and the potential exacerbation of LT disparities. Our aim was to design, perform, and examine the results of a simulated selection of candidates for LT for AH. Medical histories, psychosocial profiles and scores, and outcomes of 4 simulation candidates were presented and discussed at 2 multidisciplinary societal conferences with real-time polling of participant responses. Candidate psychosocial profiles represented a wide spectrum of alcohol relapse risk. The predictive accuracy of four psychosocial scores, Dallas consensus criteria, sustained alcohol use post-LT, Stanford Integrated Psychosocial Assessment for Transplant, and QuickTrans, were assessed. Overall, 68 providers, mostly academic transplant hepatologists, participated in the simulation. Using a democratic process of selection, a significant majority from both simulations voted to accept the lowest psychosocial risk candidate for LT (72% and 85%) and decline the highest risk candidate (78% and 90%). For the 2 borderline-risk candidates, a narrower majority voted to decline (56% and 65%; 64% and 82%). Two out of 4 patients had post-LT relapse. Predictive accuracies of Dallas, Stanford Integrated Psychosocial Assessment for Transplant, and Quicktrans scores were 50%, while sustained alcohol use post-LT was 25%. The majority of voting outcomes were concordant with post-LT relapse in 3 out of 4 patients. When defining "success" in LT for AH, providers prioritized allograft health and quality of life rather than strict abstinence. In this simulation of LT for AH using a democratic process of selection, we demonstrate its potential as a learning model to evaluate the accuracy of psychosocial scores in predicting post-LT relapse and the concordance of majority voting with post-LT outcomes. Provider definitions of "success" in LT for AH have shifted toward patient-centered outcomes.

The novel SALT-M score predicts 1-year post-transplant mortality in patients with severe acute-on-chronic liver failure.

BACKGROUND & AIMS: Twenty-eight-day mortality ranges from 30-90% in patients with acute-on-chronic liver failure grades 2/3 (severe ACLF). Though liver transplantation (LT) has demonstrated a survival benefit, the scarcity of donor organs and uncertainty regarding post-LT mortality among patients with severe ACLF may cause hesitancy. We developed and externally validated a model to predict 1-year post-LT mortality in severe ACLF, called the Sundaram ACLF-LT-Mortality (SALT-M) score, and estimated the median length of stay (LoS) after LT (ACLF-LT-LoS). METHODS: In 15 LT centers in the US, we retrospectively identified a cohort of patients with severe ACLF transplanted between 2014-2019, followed up to Jan'2022. Candidate predictors included demographics, clinical and laboratory values, and organ failures. We selected predictors in the final model using clinical criteria and externally validated them in two French cohorts. We provided measures of overall performance, discrimination, and calibration. We used multivariable median regression to estimate LoS after adjusting for clinically relevant factors. RESULTS: We included 735 patients, of whom 521 (70.8%) had severe ACLF (120 ACLF-3, external cohort). The median age was 55 years, and 104 with severe ACLF (19.9%) died within 1-year post-LT. Our final model included age >50 years, use of 1/≥2 inotropes, presence of respiratory failure, diabetes mellitus, and BMI (continuous). The c-statistic was 0.72 (derivation) and 0.80 (validation), indicating adequate discrimination and calibration based on the observed/expected probability plots. Age, respiratory failure, BMI, and presence of infection independently predicted median LoS. CONCLUSIONS: The SALT-M score predicts mortality within 1-year after LT in patients with ACLF. The ACLF-LT-LoS score predicted median post-LT stay. Future studies using these scores could assist in determining transplant benefits. IMPACT AND IMPLICATIONS: Liver transplantation (LT) may be the only life-saving procedure available to patients with acute-on-chronic liver failure (ACLF), but clinically instability can augment the perceived risk of post-transplant mortality at 1 year. We developed a parsimonious score with clinically and readily available parameters to objectively assess 1-year post-LT survival and predict median length of stay after LT. We developed and externally validated a clinical model called the Sundaram ACLF-LT-Mortality score in 521 US patients with ACLF with 2 or ≥3 organ failure(s) and 120 French patients with ACLF grade 3. The c-statistic was 0.72 in the development cohort and 0.80 in the validation cohort. We also provided an estimation of the median length of stay after LT in these patients. Our models can be used in discussions on the risks/benefits of LT in patients listed with severe ACLF. Nevertheless, the score is far from perfect and other factors, such as patient's preference and center-specific factors, need to be considered when using these tools.

Emerging Biomarkers in Alcohol-associated Hepatitis.

Alcohol-associated hepatitis (AH) is a clinical syndrome of jaundice, abdominal pain, and anorexia due to prolonged heavy alcohol intake. AH is associated with changes in gene expression, cytokines, immune response, and the gut microbiome. There are limited biomarkers to diagnose and prognosticate in AH, but several non-invasive biomarkers are emerging. In this review, clinical risk-stratifying algorithms, promising AH biomarkers like cytokeratin-18 fragments, genetic polymorphisms, and microRNAs will be reviewed.

Early Liver Transplantation for Severe Alcohol-Associated Hepatitis and a History of Prior Liver Decompensation.

INTRODUCTION: In the published studies of early liver transplantation (LT) for alcohol-associated hepatitis (AH), patients with a prior liver decompensation are excluded. The appropriateness of this criteria is unknown. METHODS: Among 6 American Consortium of Early Liver Transplantation for Alcohol-Associated Hepatitis sites, we included consecutive early LT for clinically diagnosed AH between 2007 and 2020. Patients were stratified as first vs prior history of liver decompensation, with the latter defined as a diagnosis of ascites, hepatic encephalopathy, variceal bleeding, or jaundice, and evidence of alcohol use after this event. Adjusted Cox regression assessed the association of first (vs prior) decompensation with post-LT mortality and harmful (i.e., any binge and/or frequent) alcohol use. RESULTS: A total of 241 LT recipients (210 first vs 31 prior decompensation) were included: median age 43 vs 38 years ( P = 0.23), Model for End-Stage Liver Disease Sodium score of 39 vs 39 ( P = 0.98), and follow-up after LT 2.3 vs 1.7 years ( P = 0.08). Unadjusted 1- and 3-year survival among first vs prior decompensation was 93% (95% confidence interval [CI] 89%-96%) vs 86% (95% CI 66%-94%) and 85% (95% CI 79%-90%) vs 78% (95% CI 57%-89%). Prior (vs first) decompensation was associated with higher adjusted post-LT mortality (adjusted hazard ratio 2.72, 95% CI 1.61-4.59) and harmful alcohol use (adjusted hazard ratio 1.77, 95% CI 1.07-2.94). DISCUSSION: Prior liver decompensation was associated with higher risk of post-LT mortality and harmful alcohol use. These results are a preliminary safety signal and validate first decompensation as a criterion for consideration in early LT for AH patients. However, the high 3-year survival suggests a survival benefit for early LT and the need for larger studies to refine this criterion. These results suggest that prior liver decompensation is a risk factor, but not an absolute contraindication to early LT.

Artificial intelligence to identify harmful alcohol use after early liver transplant for alcohol-associated hepatitis.

Early liver transplantation (LT) for alcohol-associated hepatitis (AH) is the fastest growing indication for LT, but prediction of harmful alcohol use post-LT remains limited. Among 10 ACCELERATE-AH centers, we examined psychosocial evaluations from consecutive LT recipients for AH from 2006 to 2017. A multidisciplinary panel used content analysis to develop a maximal list of psychosocial variables. We developed an artificial intelligence model to predict post-LT harmful alcohol use. The cohort included training (N = 91 among 8 centers) and external validation (N = 25 among 2 centers) sets, with median follow-up of 4.4 (IQR 3.0-6.0) years post-LT. In the training set, AUC was 0.930 (95%CI 0.862-0.998) with positive predictive value of 0.891 (95%CI 0.620-1.000), internally validated through fivefold cross-validation. In the external validation set, AUC was 0.692 (95%CI 0.666-0.718) with positive predictive value of 0.82 (95%CI 0.625-1.000). The model identified specific variables related to social support and substance use as highly important to predict post-LT harmful alcohol use. We retrospectively developed and validated a model that identified psychosocial profiles at LT predicting harmful alcohol use post-LT for AH. This preliminary model may inform selection and post-LT management for AH and warrants prospective evaluation in larger studies among all alcohol-associated liver disease being considered for early LT.

Extensive Health Care Utilization and Costs of an Early Liver Transplantation Program for Alcoholic Hepatitis.

Early liver transplantation (LT) for severe alcoholic hepatitis (AH) is a rescue therapy for highly selected patients with favorable psychosocial profiles not responding to medical therapy. Given the expected increase of AH candidate referrals requiring complex care and comprehensive evaluations, increased workload and cost might be expected from implementing an early LT program for AH but have not been determined. Some centers may also view AH as a strategy to expeditiously increase LT volume and economic viability. The aim of this study was to determine the health care use and costs of an early LT program for AH. Analyses of prospective databases of AH, interhospital transfers, and the hospital accounting system at a single center were performed from July 2011 to July 2016. For 5 years, 193 patients with severe AH were evaluated at our center: 143 newly referred transfers and 50 direct admissions. Annual increases of 13% led to 2 to 3 AH transfers/month and AH becoming the top reason for transfer. There were 169 (88%) nonresponders who underwent psychosocial evaluations; 15 (9%) underwent early LT. The median cost of early LT was $297,422, which was highly correlated with length of stay (r = 0.83; P < 0.001). Total net revenue of the program from LT admission to 90 days after LT was -$630,305 (-5.0% revenue), which was inversely correlated with MELD score (r = -0.70; P = 0.004) and yielded lower revenue than a contemporaneous LT program for acute-on-chronic liver failure (ACLF; $118,168; 1.4% revenue; P = 0.001). The health care use and costs of an early LT program for AH are extensive and lifesaving with marginally negative net revenue. Significantly increasing care of severe AH patients over 5 years resulted in increased LT volume, but at a lower rate than ACLF, and without improving economic outcomes due to high MELD and prolonged length of stay.

Patterns of Alcohol Use After Early Liver Transplantation for Alcoholic Hepatitis.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcoholic hepatitis (AH) is lifesaving but concerns regarding return to harmful alcohol use remain. We sought to identify distinct patterns of alcohol use post-LT to inform pre-LT candidate selection and post-LT addiction care. METHODS: Detailed post-LT alcohol use data was gathered retrospectively from consecutive patients with severe AH at 11 ACCELERATE-AH sites from 2006-2018. Latent class analysis identified longitudinal patterns of alcohol use post-LT. Logistic and Cox regression evaluated associations between patterns of alcohol use with pre-LT variables and post-LT survival. A microsimulation model estimated the effect of selection criteria on overall outcomes. RESULTS: Of 153 LT recipients, 1-, 3-, and 5-year survival were 95%, 88% and 82%. Of 146 LT recipients surviving to home discharge, 4 distinct longitudinal patterns of post-LT alcohol use were identified: Pattern 1 [abstinent](n = 103; 71%), pattern 2 [late/non-heavy](n = 9; 6.2%), pattern 3 [early/non-heavy](n = 22; 15%), pattern 4 [early/heavy](n = 12; 8.2%). One-year survival was similar among the 4 patterns (100%), but patients with early post-LT alcohol use had lower 5-year survival (62% and 53%) compared to abstinent and late/non-heavy patterns (95% and 100%). Early alcohol use patterns were associated with younger age, multiple prior rehabilitation attempts, and overt encephalopathy. In simulation models, the pattern of post-LT alcohol use changed the average life-expectancy after early LT for AH. CONCLUSIONS: A significant majority of LT recipients for AH maintain longer-term abstinence, but there are distinct patterns of alcohol use associated with higher risk of 3- and 5-year mortality. Pre-LT characteristics are associated with post-LT alcohol use patterns and may inform candidate selection and post-LT addiction care.

COVID-19 Aftershocks on Alcohol-Associated Liver Disease: An Early Cross-Sectional Report From the U.S. Epicenter.

Experts have forewarned about the coronavirus disease 2019 (COVID-19) pandemic environment fomenting the rising incidence of alcohol use disorder (AUD) and alcohol-associated liver disease (ALD). We performed a cross-sectional study of ALD at our liver transplantation (LT) center, located in the initial U.S. epicenter, New York City. Centered around the "stay at home" order date in New York state, March 22, 2020, we defined three time periods: "pre-COVID" (January 1, 2020-March 21, 2020), "COVID-quarantine" (March 22, 2020-April 22, 2020), and "declining-COVID" (April 23, 2020-August 25, 2020). We found a 62% increase in interhospital patient transfers for ALD from pre-COVID (20 of 93, 21%) to the declining-COVID period (43 of 127, 34%). Our inpatient liver census with ALD also increased: 38% pre-COVID, 45% COVID-quarantine, and 49% declining-COVID. Among 30 patients with severe alcoholic hepatitis (AH) not responding to medical therapy since March 22, 2020, 9 underwent early LT for AH (16% of the total number of early LT during our 8-year program). Three of 9 early-LT recipients reported specific COVID-related stressors. All 25 previous LT recipients with established abstinence pre-COVID maintained abstinence at follow-up visits during the declining-COVID period. Of the 6 recipients with sustained alcohol use within 6 months before March 22, 2020, half regained abstinence during the declining-COVID period. Our findings help confirm the predictions of rising AUD and ALD as an immediate consequence of the COVID-19 pandemic. This aftershock particularly affected ethnically diverse patients with ALD with high inpatient mortality, reflecting the disproportionate impact of COVID-19 on underserved and minority populations. Alcohol relapse did not occur in long-term early LT for AH recipients during the time of COVID-19. This lends further support to AH being a viable indication for LT, with recipients able to demonstrate ongoing resilience in the face of this unprecedented universal stressor.

Current and Future Biomarkers in Alcoholic Hepatitis.

Alcoholic hepatitis (AH) is a clinical syndrome of jaundice, abdominal pain, and anorexia due to prolonged heavy alcohol intake, and is associated with alterations in gene expression, cytokines, immune response, and the gut microbiome. Currently, we have limited biomarkers to diagnose and prognosticate in AH, but there are many novel noninvasive biomarkers under development. We evaluate the currently used algorithms to risk-stratify in AH (such as the Maddrey modified discriminant function), and discuss novel biomarkers in development, such as breath biomarkers, microRNAs, cytokeratin-18 fragments, and the AshTest. We also review the characteristics of an ideal biomarker in AH.

A protocol for the management of hyponatremia peri-liver transplant reduces post-transplant neurological complications.

Rapid changes in serum sodium (ΔSNa) peri-liver transplant (LT) predispose to post-LT neurological complications (NC). We aimed to assess whether implementation of a protocol directed at limiting peri-LT ΔSNa reduced post-LT NC. A retrospective single-center review of adult LT recipients from 1/2016 to 10/2017 was performed. Patients with hyponatremia (SNa < 135 mEq/L) within 7 days of LT were analyzed in two eras: pre-protocol (1/2016-9/2016) and post-protocol (10/2016-10/2017). The primary outcome was the development of NC within 1 month of LT. Perioperative ΔSNa (ΔSNaPost-LT) was assessed as a secondary outcome. Among 85 and 107 patients who underwent LT pre- and post-protocol, 39 (46%) and 42 (39%) were hyponatremic within 7 days of LT, respectively. Significantly fewer patients in the post-protocol era developed NC vs. pre-protocol (7.1% vs. 25.6%, p = .02). Additionally, fewer LT recipients in the post-protocol era developed ΔSNaPost-LT ≥ 10 mEq/L (9.5% vs. 30.7%, p = .02). Intraoperatively, more patients post-protocol received hypotonic saline (33.3% vs. 2.6%, p < .01). Multivariable logistic regression revealed that transplantation in the post-protocol era was associated with significantly reduced odds (odds ratio 0.11, 95% confidence interval 0.01-0.50) of developing NC. In conclusion, the implementation of a multidisciplinary protocol aimed at reducing ΔSNa peri-LT was independently associated with a reduction in post-LT NC.

Provider Attitudes and Practices for Alcohol Screening, Treatment, and Education in Patients With Liver Disease: A Survey From the American Association for the Study of Liver Diseases Alcohol-Associated Liver Disease Special Interest Group.

BACKGROUND & AIMS: While abstinence-promoting behavioral and pharmacotherapies are part of the therapeutic foundation for alcohol use disorder (AUD) and alcohol-associated liver disease (ALD), these therapies, along with alcohol screening and education, are often underutilized. Our aim was to examine provider attitudes and practices for alcohol screening, treatment and education in patients with liver disease. METHODS: We conducted a survey of primarily (89%) hepatology and gastroenterology providers within (80%) and outside the United States (20%). Surveys were sent to 921 providers with 408 complete responses (44%), of whom 343 (80%) work in a tertiary liver transplant center. RESULTS: While alcohol screening rates in liver disease patients was nearly universal, less than half of providers reported practicing with integrated addiction providers, using alcohol biomarkers and screening tools. Safe alcohol use by liver disease patients was felt to exist by 40% of providers. While 60% of providers reported referring AUD patients for behavioral therapy, 71% never prescribed AUD pharmacotherapy due to low comfort (84%). Most providers (77%) reported low addiction education and 90% desired more during GI/hepatology fellowship training. Amongst prescribers, baclofen was preferred, but with gaps in pharmacotherapy knowledge. Overall, there was low adherence to the 2019 AASLD practice guidance for ALD, although higher in hepatologists and experienced providers. CONCLUSIONS: While our survey of hepatology and gastroenterology providers demonstrated higher rates of alcohol screening and referrals for behavioral therapy, we found low rates of prescribing AUD pharmacotherapy due to knowledge gaps from insufficient education. Further studies are needed to assess interventions to improve provider alignment with best practices for treating patients with AUD and ALD.