The Survival Benefit of Re-abstinence After Harmful Alcohol Use Following Early Liver Transplant for Severe Alcohol-Associated Hepatitis: A Multi-Center ACCELERATE Study.

BACKGROUND AND AIMS: Early (i.e. without mandated period of abstinence) liver transplant (LT) for alcohol-associated hepatitis (AH) is the fastest growing indication for LT in the US and Europe. Harmful alcohol use post-LT is associated with poor outcomes but the distinction of establishing abstinence after return to drinking (i.e. re-abstinence) is understudied. This study aims to characterize the survival outcomes of achieving re-abstinence after post-LT harmful alcohol use. METHODS: We analyzed early LT recipients from 12 US LT centers between 2006-2021. 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 >20ng/mL. Re-abstinence was defined as >12 consecutive months without harmful alcohol use following harmful alcohol use. RESULTS: Among 347 LT recipients (64% male, median age 43, median MELD-Na 38) with median post-LT follow-up of 2.2 years (IQI 1.1 - 3.6), 276 (80%) recipients had no evidence of harmful alcohol use, 35 (10%) recipients had re-abstinence, and 36 (10%) recipients had continued harmful alcohol use without re-abstinence. Five-year predicted survival, adjusted for age, sex, MELD-Na score, was lowest among LT recipients with continued harmful alcohol use (77%), but similar among those with no harmful use (93%) and re-abstinence (94%). CONCLUSIONS: Achieving re-abstinence after post-LT harmful alcohol use is associated with similar five-year post-LT survival compared to those without evidence of post-LT harmful alcohol use. Our findings highlight the importance of early detection and treatment of post-LT alcohol use.

Faecal proteomics links neutrophil degranulation with mortality in patients with alcohol-associated hepatitis.

OBJECTIVE: Patients with alcohol-associated hepatitis (AH) have a high mortality. Alcohol exacerbates liver damage by inducing gut dysbiosis, bacterial translocation and inflammation, which is characterised by increased numbers of circulating and hepatic neutrophils. DESIGN: In this study, we performed tandem mass tag (TMT) proteomics to analyse proteins in the faeces of controls (n=19), patients with alcohol-use disorder (AUD; n=20) and AH (n=80) from a multicentre cohort (InTeam). To identify protein groups that are disproportionately represented, we conducted over-representation analysis using Reactome pathway analysis and Gene Ontology to determine the proteins with the most significant impact. A faecal biomarker and its prognostic effect were validated by ELISA in faecal samples from patients with AH (n=70), who were recruited in a second and independent multicentre cohort (AlcHepNet). RESULT: Faecal proteomic profiles were overall significantly different between controls, patients with AUD and AH (principal component analysis p=0.001, dissimilarity index calculated by the method of Bray-Curtis). Proteins that showed notable differences across all three groups and displayed a progressive increase in accordance with the severity of alcohol-associated liver disease were predominantly those located in neutrophil granules. Over-representation and Reactome analyses confirmed that differentially regulated proteins are part of granules in neutrophils and the neutrophil degranulation pathway. Myeloperoxidase (MPO), the marker protein of neutrophil granules, correlates with disease severity and predicts 60-day mortality. Using an independent validation cohort, we confirmed that faecal MPO levels can predict short-term survival at 60 days. CONCLUSIONS: We found an increased abundance of faecal proteins linked to neutrophil degranulation in patients with AH, which is predictive of short-term survival and could serve as a prognostic non-invasive marker.

Relationship between updated MELD and prognosis in alcohol-associated hepatitis: Opportunities for more efficient trial design.

BACKGROUND: Alcohol-associated hepatitis (AH) is associated with significant mortality. Model for End-Stage Liver Disease (MELD) score is used to predict short-term mortality and aid in treatment decisions. MELD is frequently updated in the course of AH. However, once the most updated MELD is known, it is uncertain if previous ones still have prognostic value, which might be relevant for transplant allocation and trial design. We aimed to investigate the predictive performance of updated MELDs in a prospectively collected cohort of patients with AH by the InTeam consortium. METHODS: Three hundred seven patients (with 859 MELD values within 60 d of admission) fulfilled the inclusion criteria. The main endpoint was time to death or transplant up to 90 days. We used a joint model approach to assess the predictive value of updated MELDs. RESULTS: Updated MELD measurements had a strong prognostic value for death/transplant (HR: 1.20, 95% CI: 1.14-1.27) (p < 0.0001). Previous MELD values did not add predictive value to the most current MELD. We also showed that MELD at day 28 (MELD28) had a significant predictive value for subsequent mortality/transplant in a landmark analysis (HR: 1.18, 95% CI: 1.12-1.23). We show that the use of an ordinal scale including death, transplant, and MELD28 as a trial outcome could substantially reduce the sample size required to demonstrate short-term benefit of an intervention. CONCLUSION: We show that updated MELDs during the trajectory of AH predict subsequent mortality or the need for transplant. MELD28 inclusion in an ordinal outcome (together with death or transplant) could increase the efficiency of randomized controlled trials.

Designing clinical trials to address alcohol use and alcohol-associated liver disease: an expert panel Consensus Statement.

Most patients with alcohol-associated liver disease (ALD) engage in heavy drinking defined as 4 or more drinks per day (56 g) or 8 (112 g) or more drinks per week for women and 5 or more drinks per day (70 g) or 15 (210 g) or more drinks per week for men. Although abstinence from alcohol after diagnosis of ALD improves life expectancy and reduces the risk of decompensation of liver disease, few studies have evaluated whether treatment of alcohol use disorders will reduce progression of liver disease and improve liver-related outcomes. In November 2021, the National Institute of Alcohol Abuse and Alcoholism commissioned a task force that included hepatologists, addiction medicine specialists, statisticians, clinical trialists and members of regulatory agencies to develop recommendations for the design and conduct of clinical trials to evaluate the effect of alcohol use, particularly treatment to reduce or eliminate alcohol use in patients with ALD. The task force conducted extensive reviews of relevant literature on alcohol use disorders and ALD. Findings were presented at one in-person meeting and discussed over the next 16 months to develop the final recommendations. As few clinical trials directly address this topic, the 28 recommendations approved by all members of the task force represent a consensus of expert opinions.

Early Liver Transplant for Alcohol-associated Liver Disease Has Excellent Survival but Higher Rates of Harmful Alcohol Use.

BACKGROUND & AIMS: Early liver transplantation (LT) for alcohol-associated liver disease (ALD) has increased worldwide. Short-term outcomes have been favorable, but data on longer-term outcomes are lacking. METHODS: Single-center retrospective study of primary LT recipients between 2010 and 2020, with follow-up through July 1, 2022. Survival analysis was performed using log rank, Cox models, and Kaplan-Meier method. Cox models were created to identify variables associated with mortality; logistic regression to identify variables associated with post-LT alcohol use. RESULTS: Of 708 patients who underwent LT, 110 (15.5%) had ALD and abstinence <6 months prior to LT (ELT), 234 (33.1%) had ALD and alcohol abstinence >6 months (SLT), and 364 (51.4%) had non-ALD diagnoses. Median follow-up was 4.6 years (interquartile range, 2.6-7.3 years). ELT recipients were younger (P = .001) with median abstinence pre-LT of 61.5 days. On adjusted Cox model, post-LT survival was similar in ELT and SLT (hazard ratio [HR], 1.31; P = .30) and superior to non-ALD (HR, 1.68; P = .04). Alcohol use (40.9% vs 21.8%; P < .001) and harmful alcohol use (31.2% vs 16.0%; P = .002) were more common in ELT recipients. Harmful alcohol use was associated with post-LT mortality on univariate (HR, 1.69; P = .03), but not multivariable regression (HR, 1.54; P = .10). Recurrence of decompensated ALD trended toward more common in ELT (9.1% vs 4.4%; P = .09). Greater than 6 months pre-LT abstinence was associated with a decreased risk of harmful alcohol use (odds ratio, 0.42; P = .001), but not in a multivariable model (odds ratio, 0.71; P = .33). CONCLUSIONS: Patients who undergo ELT for ALD have similar or better survival than other diagnoses in the first 10 years after LT despite a higher incidence of post-LT alcohol use.

Severe Elevated Bile Acids in Early Pregnancy.

Intrahepatic cholestasis of pregnancy (ICP) typically presents in the second half of pregnancy. Severe ICP is associated with increased risk of stillbirth. Little is known regarding elevated bile acids in the first trimester. We present a case of severely elevated bile acids in the first trimester, resistant to conservative management, in a patient with pre-existing cholestatic liver disease and aortic valve disease requiring anticoagulation. Therapeutic plasma exchange was used. In those with pre-existing cholestatic disease, early bile acid elevation is likely distinct from ICP, and conservative strategies may not be useful. In addition, therapeutic enoxaparin appears safe in therapeutic plasma exchange.

Serum aryl hydrocarbon receptor activity is associated with survival in patients with alcohol-associated hepatitis.

BACKGROUND AND AIMS: Patients with alcohol-associated hepatitis (AH) have an altered fecal metabolome, including reduced microbiota-derived tryptophan metabolites, which function as ligands for aryl hydrocarbon receptor (AhR). The aim of this study was to assess serum AhR ligand activity in patients with AH. APPROACH AND RESULTS: The study included 74 controls without AUD, 97 patients with AUD, and 330 patients with AH from 2 different multicenter cohorts (InTeam: 134, AlcHepNet: 196). Serum AhR activity was evaluated using an AhR reporter assay with HepG2-Lucia cells incubated with serum for 24 hours. Serum AhR activity was significantly higher in patients with AH compared with both controls (1.59 vs. 0.96-fold change, p < 0.001) and patients with AUD (1.59 vs. 0.93, p < 0.001). In both AH cohorts, patients with AhR activity ≥ 2.09 had significantly lower cumulative survival rates at 30, 60, 90, and 180 days compared to those with AhR activity < 2.09. When serum AhR activity was used to further stratify patients with severe AH, the cumulative 30, 60, 90, and 180-day survival rates for patients with severe AH and the AhR activity ≥ 2.09 group were all significantly lower than those with an AhR activity < 2.09 group. CONCLUSIONS: Serum AhR activity was significantly higher in patients with AH compared with controls and individuals with AUD, and this increased activity was associated with higher mortality. Consequently, serum AhR activity holds potential as a prognostic marker.

Evaluating the effectiveness of a clinical nurse specialist triage role in a specialist palliative care community service.

BACKGROUND: In 2017, a clinical nurse specialist (CNS) triaging role was created within a specialist palliative care community service (SPCCS) in Ireland to enhance the triage process. The aim of this study is to evaluate the effectiveness of the role regarding data collection and reporting. Structured feedback from healthcare professionals (HCPs) was obtained on the effects, challenges and sustainability of this role. METHODS: This study used a mixed-methods approach. A quantitative analysis of referrals triaged by the SPCCS CNS over 2 years (2018-2019) was performed. Two focus groups with HCP's within the same service were completed in January 2020 and one-to-one interviews were conducted. The quantitative and qualitative results were merged using a triangulation protocol. RESULTS: In 2017, new health service executive (HSE) standards to categorise the urgency of patient assessment were introduced. Quantitatively, an improvement within the triage process was seen, with an increase in compliance with national access standards. In 2018, compliance was 89.1%. In 2019, this was 96.8%, an improvement of 7.7%. A data discrepancy of 9.5% of referrals was noted over the first 9 months of 2018. After this, data documentation and congruency were seen to improve for the final 3 months of 2018 to 100% and remained at 100%. Qualitative data highlighted the benefits and challenges of the Triage CNS role. Mixed-methods correlation revealed corroboration between both using a triangulation protocol. CONCLUSION: The triage CNS role was pivotal as an initial point of referral contact. Increased compliance with national access standards occurred resulting in improvements in case and case-load management, information gathering, documentation, data collection and analysis.

Prognostic models in alcohol-related liver disease and alcohol-related hepatitis.

Alcohol-associated liver disease (ALD) and alcohol-associated hepatitis (AH) are dynamic disorders whose prognosis can be challenging to determine. A number of prognostic models have been developed to determine likelihood of death, when to refer for liver transplant (LT) and the role for glucocorticoids. Often these models were created with a specific application in mind but were found to have additional applications with further study. Those prognostic models that have stood the test of time are easy to use, have clear interpretations and employ objective parameters. These parameters most often include total bilirubin, INR and creatinine among other data points. Ideally, these models could be utilized at all phases of disease but in most, it is important for clinicians to consider drinking history and how it might alter the determined scores. Herein we provide a brief review of prognostic models in ALD and AH and provide practical tips and considerations to successfully make use of these tools in a clinical setting.

The potential role of infusions of T regulatory cells in inducing and maintaining liver allograft tolerance.

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Virtual reality use and patient outcomes in palliative care: A scoping review.

Objective: Virtual reality is increasingly used in healthcare settings. Potentially, it's use in palliative carecould have a positive impact; however, there is limited evidence on the scope, purpose and patient outcomes relating to virtual reality use in this context. The objective of this scoping review is to chart the literature on virtual reality use in palliative care, identifying any evidence relating to biopsychosocial patient outcomes which could support its use in practice. Methods: A scoping review of the literature, involving . a systematic search across 10 electronic bibliographic databases in December 2021, . Eligibility criteria were primary research studies, of any research designwithin a 10-year timeframe, which reported on virtual reality use and patient outcomes in palliative care. A total of 993 papers were identified, andcomprehensive screening resulted in 10 papers for inclusion. Results: This scoping review identified 10 papers addressing virtual reality in palliative care, published within a three-year timeframe 2019-2021. Research methodologies included mixed methods, quantitative and qualitative. The evidence highlightsvirtual reality use with patients receiving palliative care in a variety of settings, and data around useability, feasibility and acceptability is positive. However, the evidence regarding biopsychosocial patient outcomes linked to virtual reality use is limited. Conclusion: Virtual reality is gathering momentum in palliative care and is potentially a helpful intervention; however more research is needed to underpin the evidence base supporting its application, particularly in understanding the impact on biopsychosocial patient outcomes and ascertaining the best approach for measuring intervention effectiveness.

Early liver transplantation for severe acute alcohol-related hepatitis after more than a decade of experience.

In patients with severe acute alcohol-related hepatitis not responding to medical therapy, early liver transplantation (LT) represents the only effective therapy and, when performed within strict and well-defined protocols, it is associated with a clear survival benefit and acceptable rates of return to alcohol use after transplantation. However, there is still high variability in access to LT for patients with severe alcohol-related hepatitis, mainly due to a persistent overemphasis in the pre-LT evaluation on duration of pre-transplant abstinence and the stigma that patients with alcohol-related liver disease often experience, leading to marked inequity of access to this potentially lifesaving procedure and negative health outcomes. Therefore, there is an increasing need for prospective multicentre studies focusing on pre-transplant selection practices and on better interventions to treat alcohol use disorder after LT.

Specialist palliative care out of hours telephone advice in Ireland: a national survey.

OBJECTIVES: In 2015 the All-Ireland Institute of Hospice and Palliative Care identified access to specialist palliative care (SPC) advice out of hours (OOH) as their number one research priority. Receiving appropriate advice in response to palliative care needs OOH can address a patient/family's concerns and prevent unnecessary hospital attendances.The aim of this study was to describe the current model of SPC OOH advice in the units that run this service, and gain a greater understanding of the nature of calls received by these services. METHODS: A national online survey was sent to staff providing OOH advice to patients with SPC needs and a second survey was sent to the managers of the organisations within Ireland. Surveys were emailed with a link to managers of both inpatient and community services who provide SPC. RESULTS: 78 clinical staff who provide OOH telephone advice responded to the survey and there were 23 responses to the managers' survey. The most common type of call received was in relation to symptom management (97%); however, 73% of staff indicated that they had no specific training in giving OOH advice over the phone and furthermore 44% of respondents felt ill equipped and uncomfortable giving OOH advice for a number of reasons. CONCLUSIONS: This survey has highlighted the need for support and training to the staff providing OOH SPC advice and that a set of standards to guide practice would be useful to this cohort of staff.

Using a validated case mix tool for use in the telephone-assisted triage of patients in a specialist palliative care community setting: a consecutive case series.

OBJECTIVES: Allocating resources in palliative care is challenging due to the nature of life-limiting illness coupled with the propensity for significant physical symptoms and psychological distress. At present, there is no established system for triaging referrals and prioritising resource allocation.This study aimed to evaluate the feasibility of using a case mix assessment tool for telephone-assisted triaging of referrals to a specialist palliative care service. This assessed a patient's phase of illness, Problem Severity Score (PSS) for complexity of symptom burden and psychological distress, and functional status. METHODS: Using a prospective consecutive case series approach, 450 referrals to community palliative care over a 6-month period were assessed. Scores for phase of illness, PSS and functional status were assessed at triage, as was the triage category of urgency of response. RESULTS: Analysis demonstrated that phase of illness corresponds with triage category, with terminal or unstable phase patients significantly associated with urgent (category 1) referrals and highest priority for review. Decreased functional status and high PSS were useful predictors for increased urgency of referral. CONCLUSIONS: These results demonstrate that this case mix tool could assist in the telephone assessment and triage of referrals to community palliative care.

Multicentered study of patient outcomes after declined for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Early liver transplantation for alcohol-associated hepatitis is controversial in part because patients may recover, and obviate the need for liver transplantation. METHODS: In this retrospective study among 5 ACCELERATE-AH sites, we randomly sampled patients evaluated and then declined for liver transplantation for alcohol-associated hepatitis. All had Model of End-Stage Liver Disease (MELD) >20 and <6 months of abstinence. Recompensation was defined as MELD <15 without variceal bleeding, ascites, or overt HE requiring treatment. Multilevel mixed effects linear regression was used to calculate probabilities of recompensation; multivariable Cox regression was used for mortality analyses. RESULTS: Among 145 patients [61% men; median abstinence time and MELD-Na was 33 days (interquartile range: 13-70) and 31 (interquartile range: 26-36), respectively], 56% were declined for psychosocial reasons. Probability of 30-day, 90-day, 6-month, and 1-year survival were 76% (95% CI, 68%-82%), 59% (95% CI, 50%-66%), 49% (95% CI, 40%-57%), and 46% (95% CI, 37%-55%), respectively. Probability of 1-year recompensation was low at 10.0% (95% CI, 4.5%-15.4%). Among patients declined because of clinical improvement, 1-year probability of recompensation was 28.0% (95% CI, 5.7%-50.3%). Among survivors, median MELD-Na at 30 days, 90 days, and 1-year were 29 (interquartile range: 22-38), 19 (interquartile range : 14-29), and 11 (interquartile range : 7-17). Increased MELD-Na (adjusted HR: 1.13, p <0.001) and age (adjusted HR: 1.03, p <0.001) were associated with early (≤90 d) death, and only history of failed alcohol rehabilitation (adjusted HR: 1.76, p =0.02) was associated with late death. CONCLUSIONS: Liver recompensation is infrequent among severe alcohol-associated hepatitis patients declined for liver transplantation. Higher MELD-Na and age were associated with short-term mortality, whereas only history of failed alcohol rehabilitation was associated with long-term mortality. The distinction between survival and liver recompensation merits further attention.