Evolving trends and outcomes on the US liver transplant waitlist of alcohol-associated hepatitis patients with very high MELD scores.

Liver transplantation (LT) in patients with alcohol-associated hepatitis (AH) has rapidly increased following the coronavirus disease 2019 pandemic and the implementation of the Acuity Circle policy, raising questions of equity and utility. Waitlist mortality among high (≥37) Model for End-Stage Liver Disease LT candidates with AH and post-transplant survival were assessed with a semiparametric survival regression and a generalized linear mixed-effect model with LT centre- and listing date-level random intercepts. These models demonstrate a lower mortality for the candidates listed with AH (adjusted sub-hazard ratio .58_.72_.90 and odds ratio .44_.66_.99) when compared to other diagnoses (autoimmune hepatitis, metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis). Post-LT survival was comparable. This study highlights the limitations of current tools in characterizing the risk of mortality, and thus need for the modifications in prioritizing LT candidates with AH. Policy revision may be needed to ensure equivalent access to LT regardless of diagnosis.

A Tailored Virtual Program for Alcohol Use Disorder Treatment Among Liver Transplant Candidates and Recipients Is Feasible and Associated With Lower Post-Transplant Relapse.

BACKGROUND: Alcohol-associated liver disease (ALD) is a leading indication for liver transplant (LT) in the United States. Rates of early liver transplant (ELT) with less than 6 months of sobriety have increased substantially. Patients who receive ELT commonly have alcohol-associated hepatitis (AH) and are often too ill to complete an intensive outpatient program (IOP) for alcohol use disorder (AUD) prior to LT. ELT recipients feel alienated from traditional IOPs. METHODS: We implemented Total Recovery-LT, a tailored virtual outpatient IOP specific for patients under evaluation or waitlisted for LT who were too ill to attend community-based alcohol treatment programs. The 12-week program consisted of weekly group and individual counseling delivered by a master's level Certified Addiction Counselor trained in the basics of LT.  Treatment consisted of 12-Step Facilitation, Motivational Interviewing, and Cognitive Behavioral Therapy. We report on program design, implementation, feasibility and early outcomes. RESULTS: From March 2021 to September 2022, 42 patients (36% female, 23 in LT evaluation, 19 post-transplant) enrolled across five cohorts with 76% (32/42) completing the program. Alcohol relapse was more common among noncompleters versus those who completed the program (8/10, 80% vs. 7/32, 22%, p = 0.002). History of trauma or post-traumatic stress symptoms were associated with lower likelihood of completion. Patients' desire for continued engagement after completion led to the creation of a monthly alumni group. CONCLUSIONS: Our integrated IOP model for patients with high-risk AUD in LT evaluation or post-transplant is well-received by patients and could be considered a model for LT programs.

Utility of Lille Score in Predicting 30-Day Survival in Steroid-Treated Alcohol-Associated Hepatitis.

BACKGROUND/AIMS: In alcohol-associated hepatitis (AH), the Lille score is used to assess futility of steroids. However, the ability of the Lille score to predict 30-day survival in AH is not well-defined. Our aim is to compare the utility of the Lille score in predicting 30-day survival in those with AH treated with steroids. METHODS: Retrospective chart review of 882 patients hospitalized with AH from January 1st, 2012 through December 30th, 2019 was performed. Of these, 201 patients with severe AH met the threshold to receive steroids. Those with data to calculate Lille score < 0.45 on day 4 (n = 29) or 7 (n = 89) who continued steroids were compared to 83 patients with Lille scores ≥ 0.45 on day 4 (n = 18) or 7 (n = 65) who stopped steroids. The primary outcome was 30-day survival. For comparison, a contemporaneous matched control group was also analyzed of 110 patients who were hospitalized with severe AH, but did not receive steroids. RESULTS: In patients with Lille score < 0.45, survival was higher at 30-day when compared to those with Lille score ≥ 0.45 (94.9% vs. 80.72%; p = 0.002). The sensitivity, specificity, positive predictive value and negative predictive value of Lille score (< 0.45) to predict 30-day survival was 95%, 19%, 63%, and 73%, respectively. CONCLUSIONS: In severe AH, those with Lille score < 0.45 at day 4 or 7 have improved 30-day survival compared to those with Lille score ≥ 0.45. In those receiving steroids, Lille score has excellent sensitivity to predict 30-day survival but poor specificity.

Alcohol-Associated Liver Disease: Integrated Management With Alcohol Use Disorder.

Alcohol-associated liver disease (ALD) is the most common cause of cirrhosis and liver-related mortality in many regions worldwide. Around 75% of patients with cirrhosis are unaware of their disease until they are referred to the emergency department. An innovative, noninvasive screening approach is required for an earlier diagnosis of liver fibrosis. In patients with ALD the physician is inevitably dealing with 2 major disorders: the liver disease itself and the alcohol use disorder (AUD). Focus only on the liver disease will inevitably lead to failure because transient improvements in liver function are rapidly overturned if the patient returns to alcohol consumption. For this reason, integrated models of care provided by hepatologists and addiction specialists are an effective approach, which are, however, not widely available. There are multiple pharmacologic and non-pharmacologic therapies for AUD. Progress has recently been made in the management of patients with severe AH who have improved survival through better understanding of the concept of response to medical treatment, improved survival prediction, and the advent of early liver transplantation. The emerging concept is that listing for transplantation a patient with severe ALD could lead to adjusting the duration of abstinence according to the severity and evolution of liver dysfunction and the patient's addictive profile.

Adding Inflammatory Markers and Refining National Institute on Alcohol Abuse and Alcoholism Criteria Improve Diagnostic Accuracy for Alcohol-associated Hepatitis.

BACKGROUND & AIMS: Although histology is considered the gold standard for diagnosis of alcohol-associated hepatitis (AH), it is not required for entry into therapeutic studies if patients meet National Institute on Alcohol Abuse and Alcoholism (NIAAA) consensus criteria for probable AH. Our aim was to assess the diagnostic accuracy of NIAAA criteria against liver biopsy and to explore new criteria to enhance diagnostic accuracy for AH. METHODS: A total of 268 consecutive patients with alcohol-related liver disease with liver biopsy were prospectively included: 210 and 58 in the derivation and validation cohorts, respectively. NIAAA criteria and histological diagnosis of alcoholic steatohepatitis (ASH) were independently reviewed by clinical investigators and pathologists from Hospital Clínic and Mayo Clinic. Using biopsy-proven ASH as gold standard we determined diagnostic capability of NIAAA criteria and proposed the new improved criteria. RESULTS: In the derivation cohort, diagnostic accuracy of NIAAA for AH was modest (72%) due to low sensitivity (63%). Subjects who did not meet NIAAA with ASH at liver biopsy had lower 1-year survival compared with subjects without ASH (70% vs 90%; P < .001). NIAAAm-CRP criteria, created by adding C-reactive protein and modifying the variables of the original NIAAA, had higher sensitivity (70%), accuracy (78%), and specificity (83%). Accuracy was also higher in a sensitivity analysis in severe AH (74% vs 65%). In the validation cohort, NIAAAm-CRP and NIAAA criteria had a sensitivity of 56% vs 52% and an accuracy of 76% vs 69%, respectively. CONCLUSION: NIAAA criteria are suboptimal for the diagnosis of AH. The proposed NIAAAm-CRP criteria may improve accuracy for noninvasive diagnosis of AH in patients with alcohol-related liver disease.

Role of rifaximin in the management of alcohol-associated hepatitis: A systematic review and meta-analysis.

BACKGROUND AND AIM: Alcohol-associated hepatitis (AAH) is an acute, inflammatory liver disease with severe short-term and long-term morbidity and mortality. AAH can lead to severe complications including hepatic failure, gastrointestinal bleeding, sepsis, and the development or decompensation of cirrhosis. Rifaximin is an antibiotic that reduces bacterial overgrowth and gut translocation, and it may have a role in decreasing systemic inflammation and infection in patients with AAH. Therefore, we conducted a systematic review and meta-analysis to evaluate the role of rifaximin in the management of AAH. METHODS: A comprehensive search strategy was used to identify studies that met our inclusion criteria in Embase, MEDLINE (PubMed), Cochrane Library, Web of Science Core Collection, and Google Scholar. Outcomes of interest included rates of infection, 90-day mortality, and overall mortality between the rifaximin versus non-rifaximin group. Open Meta Analyst software was used to compute the results. RESULTS: Three studies with a total of 162 patients were included in the final meta-analysis. Of the three studies, two were randomized control trials (RCTs), and one was a case-control study. There was a significantly lower rate of infection in the rifaximin group versus the non-rifaximin group (RR: 0.331, 95% CI: 0.159-0.689, I2  = 0%, P = 0.003). There was no significant difference in 90-day mortality in the rifaximin versus non-rifaximin group (RR: 0.743, 95% CI: 0.298-1.850, I2  = 24%, P = 0.523), nor was there a significant difference in overall mortality (RR: 0.624, 95% 95% CI: 0.299-1.3, I2  = 7.1%, P = 0.208). CONCLUSIONS: The use of rifaximin in AAH is associated with a lower rate of infection rate than the non-rifaximin group. Additional research is needed to determine whether this effect is more pronounced in patients concurrently being treated with prednisolone. Differences in 90-day or overall mortality did not reach statistical significance. Further studies, particularly large randomized controlled trials, are needed to establish the role of rifaximin in AAH, especially as an adjunct therapy with prednisolone.

Prevalence, co-morbidities, and in-hospital mortality of patients hospitalized with alcohol-associated hepatitis in the United States from 2015 to 2019.

BACKGROUND: The goals of our study are to determine the most recent trends in hospitalization, mortality, and healthcare utilization among hospitalized patients with alcohol-associated hepatitis (AH) in the United States. METHODS: We examined the recent prevalence, co-morbidities, and mortality in hospitalized AH patients in the United States based on the available National Inpatient Sample (NIS) data (2015 to 2019) using appropriate International Classification of Diseases (ICD) codes. We reported our data as national estimates based on the discharge weighting variable (DISCWT). Logistic regression analyses were used to determine factors associated with mortality. RESULTS: We observed an increase in the total number of hospitalized AH patients from 110,135 in 2015 to 136,620 in 2019, which represented 386 per 100,000 total hospitalizations or 42 per 100,000 US population, which in 2019 was 328 million. Patients were a mean of 48 years old and the majority were White and male. The average length of stay was around 6 days with an overall in-hospital mortality that decreased from 4.19% in 2015 to 3.86% in 2019 (p-value for trend = <0.0001). During the 5-year study period, a total of 24,795 hospitalized AH patients died and 592,885 survived the hospital stay. Those who died were older, had a longer length of stay, and higher hospital charges during the stay. Mortality was significantly greater in patients who presented with complications from portal hypertension, those with acute renal failure, underlying cirrhosis, and sepsis. CONCLUSIONS: Our study documented the increasing prevalence of hospitalized AH patients and their significant associated healthcare costs and utilization. Our results underscore a continuing unmet and urgent need to identify effective therapies for hospitalized AH patients.

Short-term and long-term causes of death in patients with alcoholic hepatitis in Denmark.

BACKGROUND & AIMS: The incidence of acute alcoholic hepatitis is increasing, and mortality is high. However, causes of death among patients with alcoholic hepatitis have not been systematically recorded. We investigated causes of death in a population-based cohort of patients with alcoholic hepatitis who were followed for as long as 10 years. METHODS: We used the Danish National Registry of Patients to identify all patients with a first-time episode of alcoholic hepatitis from 1999 through 2008. We collected and analyzed data on 1951 patients, identifying causes of death, diagnoses of cirrhosis, and alcohol abuse. RESULTS: Of the 1951 patients, 401 died within the first 84 days after admission, and 600 died later (through December 31, 2008). Most deaths within the first 84 days after admission resulted from liver failure (40%), infections (20%), or hepatorenal syndrome (11%). Beyond 84 days, causes of deaths differed between patients with and without cirrhosis; most patients without cirrhosis (n = 326) died of causes related to alcohol abuse, whereas most patients with cirrhosis (n = 675) died of liver failure (34%), infections (16%), or variceal bleeding (11%). Cirrhosis was present in 51% of patients diagnosed with alcoholic hepatitis. Among patients without cirrhosis, 24% developed cirrhosis within 10 years; continued alcohol abuse was a strong risk factor for cirrhosis (hazard ratio, 2.14; 95% confidence interval, 1.50-3.05). The 10-year risk of a second episode of alcoholic hepatitis was 12%. CONCLUSIONS: On the basis of a study of the Danish population, the most common causes of death among patients with alcoholic hepatitis, within 84 days and within 10 years, are liver-related events and infections. Strategies are to identify and treat these complications and to reduce alcoholism.

Risk of mortality among patients with alcohol-associated hepatitis in the US from 2007 to 2021.

BACKGROUND/AIMS: Alcohol-associated hepatitis (AH) mortality and risk factors have not been carefully studied in real-world settings. We examined the rate, temporal trend, and risk factors of mortality in AH. METHODS: We conducted a cohort study of individuals with AH diagnoses using medical claims data from Optum's Clinformatics® Data Mart (CDM). Participants were individuals covered by Medicare Advantage and commercial insurance policies. Cases were identified using diagnostic codes. Cox regressions were used to estimate 90 and 180-day mortality rates by hospitalization status. RESULTS: The cohort included 32,001 patients (72% men) who had at least one year of continuous insurance coverage prior to AH diagnoses. Of these, 20,912 were hospitalized within seven days of diagnosis. Ninety and 180-day mortality rates were 12.0% (95% CI [11.6%, 12.5%]) and 16.0% (95% CI [15.4%, 16.5%]), respectively, for the hospitalized patients and 3.1% (95% CI [2.8%, 3.4%]) and 5.1% (95% CI [4.6%, 5.5%]) for the non-hospitalized patients. Pre-existing liver disease, even in a mild form, was associated with an increased risk of death. In hospitalized patients, a history of mild liver disease was associated with a 24% increase in 180-day mortality risk (HR = 1.24, 95% CI: [1.14, 1.36]). Moderate-to-severe liver disease was associated with a more than doubled risk (HR = 2.33, 95% CI: [2.12, 2.56]). CONCLUSIONS: History of liver disease was associated with significantly increased AH mortality. The finding highlights the chronic disease context of AH and suggests that prior diagnosis of liver disease should be considered for prognosis and targeted prevention.

Non-Invasive Biomarkers for Differentiating Alcohol Associated Hepatitis from Acute Decompensation in Patients with ALD.

Alcohol-associated hepatitis (AH) is the most severe form of alcohol-related liver disease. The natural course of alcohol-related liver disease is influenced by heavy alcohol consumption and abstinence periods. Differentiating between AH and decompensated cirrhosis (DC) could be extremely challenging in clinical practice due to clinical and bioclinical similarities. The severity of AH is made on bioclinical grounds, the severe form necessitating corticotherapy treatment. Liver biopsy is still the standard of care for establishing the diagnosis in atypical presentations. The pathogenesis of AH is an interplay between gene expression, cytokine dysregulation, the immune system and the gut microbiota. Non-invasive tests are increasingly and widely used for the purpose of early diagnosis and reliable prognostication. The non-invasive tests are emerging in concordance with disease pathogenesis. In this review, we describe the non-invasive tools that can distinguish AH from DC. We outline the available cut-offs and their performance in diagnosis and prognosis, as well as in assessing the treatment response to corticotherapy. Promising circulating biomarkers like keratin 18, microRNAs and sphingolipids will be in the review.

Single-cell transcriptomics of peripheral blood mononuclear cells indicates impaired immune and inflammatory responses in alcohol-associated hepatitis.

Alcohol-associated hepatitis (AH) is often diagnosed at advanced stages, and severe AH usually carries poor prognosis and high short-term mortality. In addition, it is challenging to understand the molecular mechanisms of immune dysregulation and inflammation in AH due to the cellular complexity and heterogeneity. Using single-cell RNA sequencing, previous studies found that AH causes dysfunctional innate immune response in monocytes, involving activation of pattern recognition receptors (PRRs) and cytokine signaling pathways. To better understand the coordinated systemic immune response in AH patients, we performed combined single-cell transcriptome, cell-surface protein, and lymphocyte antigen receptor analysis of peripheral blood mononuclear cell (PBMC) samples. Our results showed inflammatory cytokines and chemokines were highly expressed in AH, including IL-2, IL-32, CXC3R1 and CXCL16 in monocytes and NK cells, whereas HLA-DR genes were reduced in monocytes. In addition, we also found altered differentiation of T-helper cells (TH1 and TH17), which could further lead to neutrophil recruitment and macrophage activation. Lastly, our results also suggest impaired NK-cell activation and differentiation in AH with reduced gene expression of KLRC2 and increased gene expression of KLRG1. Our findings indicate different mechanisms may be involved in impaired immune and inflammatory responses for the cellular subtypes of the PBMCs in AH.

Development and evaluation of objective trial performance metrics for multisite clinical studies: Experience from the AlcHep Network.

BACKGROUND: Recruitment and retention are critical in clinical studies but there are limited objective metrics of trial performance. We tested if development of trial performance metrics will allow for objective evaluation of study quality. Performance metrics were developed using data from the observational cohort (OBS) and randomized clinical trial (RCT) arms of the prospective Alcoholic Hepatitis Network. METHODS: Yield-rate (%YR; eligible/screened), recruitment index (RI; mean recruitment time/patient), completion index (CI; average number of days to complete the follow-up/patient), and protocol adherence index (AI; average number of deviations/subject recruited) were determined. RESULTS: 2250 patients (1168 for OBS; 1082 for RCT) were screened across 8 sites. Recruitment in the RCT (57% target) was similar to that in the OBS (59% target). Of those screened, 743 (63.6%) subjects in the OBS and 147 (13.6%) subjects in the RCT were enrolled in the study. In OBS study, 253 (34.1%) subjects, and in the RCT, 68 (46.3%) subjects, completed the study or reached a censoring event. Across all sites (range), YR for OBS was 63.6% (41.3-98.3%) and for RCT was 13.6% (5.5-92.6%); RI for OBS was 1.66 (8.79-19.85) and for RCT was 4.05 (19.76-36.43); CI for OBS was 4.87 (22.6-118.3) and for RCT was 8.75 (27.27-161.5); and AR for OBS was 0.56 (0.08-1.04) and for RCT was 1.55 (0.39-3.21. Factors related to participants, research design, study team, and research sponsors contributed to lower performance metrics. CONCLUSIONS: Objective measures of clinical trial performance allow for strategies to enhance study quality and development of site-specific improvement plans. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT4072822 NCT03850899.

Inflammation in Alcohol-Associated Hepatitis: Pathogenesis and Therapeutic Targets.

Alcohol-associated hepatitis (AH) is an acute-on-chronic liver injury that occurs in patients with chronic alcohol-associated liver disease (ALD). Patients with severe AH have high short-term mortality and lack effective pharmacologic therapies. Inflammation is believed to be one of the key factors promoting AH progression and has been actively investigated as therapeutic targets over the last several decades, but no effective inflammatory targets have been identified so far. In this review, we discuss how inflammatory cells and the inflammatory mediators produced by these cells contribute to the development and progression of AH, with focus on neutrophils and macrophages. The crosstalk between inflammatory cells and liver nonparenchymal cells in the pathogenesis of AH is elaborated. We also deliberate the application of recent cutting-edge technologies in characterizing liver inflammation in AH. Finally, the potential therapeutic targets of inflammatory mediators for AH are briefly summarized.

Liver surface nodularity and ascites are associated with mortality risk in acute alcohol-associated hepatitis.

BACKGROUND: Acute alcohol-associated hepatitis (AH) is associated with high mortality. CT-derived liver surface nodularity (LSN) is a robust prognostic biomarker in other chronic liver diseases. The aim of this study was to determine relationships between LSN, disease severity, and mortality in AH. METHODS: Adults hospitalized with AH from January 2016 to March 2020 were included if an abdominal CT was performed between 8 weeks prior to 72 h after hospitalization. LSN was measured using quantitative methods (Liver Surface Nodularity Software version 0.88, Birmingham, AL, USA). Cox proportional hazards models, logistic regression and AUROC analysis were used to examine relationships between LSN and 180-day transplant-free survival. RESULTS: Of 386 patients hospitalized with AH during the study period, 230 had CT scans performed, and 205 met inclusion criteria. Mean transplant-free survival was 127 days (95% CI 118-137). Within each cohort, patients were grouped into low [LSN-LOW, N = 109 (53.2%)] and high [LSN-HIGH, N = 96 (46.8%)] LSN strata based on an optimal cutoff of 2.86 derived from unadjusted ROC curves. Patients with high LSN had features of portal hypertension, which included encephalopathy [53 (55.2%) vs. 43 (39.4%), p = 0.017], ascites on CT [81 (84.4%) vs. 69 (63.3%), p = 0.001] and portosystemic shunts [78 (81.2%) vs. 69 (63.3%), p = 0.003]. High LSN, ascites and MELD were independently associated with lower likelihood of 180-day transplant-free survival, and inclusion of a score assigning 1 point each for high LSN or ascites on CT (AHRADS score) to MELD enhanced diagnostic accuracy of AUROC for 180-day survival compared to MELD alone [AUROC 0.782 (95% CI 0.719-0.845) vs. 0.735 (0.667-0.802), p = 0.023]. CONCLUSIONS: CT-derived factors that include LSN and ascites are radiographic biomarkers associated with 180-day transplant-free survival in alcohol-associated hepatitis.

Inpatient Screening, Brief Intervention, and Referral to Treatment for Alcohol Use Disorder in Patients Admitted with Alcohol-associated Liver Disease Is Not Universally Implemented in Practice, But Can Reduce Readmissions for Alcohol-associated Hepatitis.

Introduction: The management of alcohol-related liver disease requires a multidisciplinary approach to treat alcohol use disorder. We aimed to determine the proportion of actively drinking patients admitted for alcohol-associated hepatitis (AAH) or decompensated alcohol-related cirrhosis (DARLC) who were offered or underwent screening, brief intervention, and referral to treatment (SBIRT) for alcohol use disorder during admission and if inpatient SBIRT is associated with reduced readmissions for alcohol-related liver disease. Methods: We conducted a retrospective cohort study of actively drinking patients admitted to our institution from January 2017 to December 2021 with AAH or DARLC. Logistic regression was used to identify factors, such as conducting SBIRT, that were associated with 30-day and 90-day readmissions for recurrent AAH or DARLC. Results: There were 120 AAH admissions (mean age 47.7 ± 13.6 years), and 177 DARLC admissions (mean age 58.2 ± 9.5 years). SBIRT was conducted in only 51.7% of AAH admissions, and 23.7% of DARLC admissions. For AAH, conducting SBIRT was associated with significantly reduced 30-day (OR 0.098, P = 0.001, 95% CI 0.024-0.408) and 90-day (OR 0.166, P = 0.003, 95% CI 0.052-0.534) readmissions. For DARLC, there was no association between conducting SBIRT and 30-day or 90-day readmissions. Conclusion: SBIRT was conducted with actively drinking patients in only 51.7% of AAH admissions and 23.7% of DARLC admissions. Patients admitted for AAH who received inpatient SBIRT had decreased 30-day and 90-day readmission rates for AAH or DARLC.

The pharmacological management of alcohol-related cirrhosis: what's new?

INTRODUCTION: Alcohol use disorder (AUD) is present in the majority of patients with alcohol-associated liver disease (ALD), which leads to about 50% of cirrhosis-related hospitalizations and over 25% of deaths worldwide. Patients with ALD often present at an advanced stage, like cirrhosis with its complications and alcohol-associated hepatitis (AH), which has high short-term mortality. Current treatments are limited, with the limited benefit of glucocorticoids only in the short-term among patients with AH, highlighting an urgent need for novel therapies. AREAS COVERED: This review applies the PIRO (Predisposition, Injury, Response, Organ dysfunction) concept to ALD, understanding an ongoing process of liver damage, and opportunities to address and halt the progression. We also highlight the significance of treating AUD to improve long-term outcomes in ALD. EXPERT OPINION: Personalized therapies targeting specific genetic profiles and multiple pathogenic pathways are crucial in managing ALD. Emerging therapies like gut-liver-brain axis modulators like fecal microbiota transplant and probiotics, interleukin-22, granulocyte-colony stimulating factor (G-CSF) and stem cells, epigenetic regulators of inflammation and regeneration are encouraging with the potential of efficacy in patients with ALD. Liver transplantation (LT) is a definitive therapy for advanced cirrhosis with increasing impetus on early LT select patients with active alcohol use.

Review article: Current indications and selection criteria for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Alcohol-associated hepatitis (AH) is a severe inflammatory form of alcohol-associated liver disease (ALD) that carries a high mortality rate. Early liver transplantation for severe AH is increasingly available. However, specific criteria for referral and selection remain a subject of debate. AIMS: To provide a narrative review of the natural history, diagnostic criteria and indications for referral for early liver transplantation for severe AH. METHODS: We searched PubMed for articles published through August 2023. Key search terms were 'alcoholic hepatitis,' 'alcohol-associated hepatitis,' 'abstinence,' 'alcohol relapse,' and 'liver transplantation.' RESULTS: Previously, a six-month period of alcohol abstinence was required before patients with ALD were considered for liver transplantation. However, studies in recent years have demonstrated that, among carefully selected patients, patients who received early transplants have much higher survival rates than patients with similarly severe disease who did not undergo transplants (77% vs. 23%). Despite these successes, early liver transplantation remains controversial, as these patients have typically not undergone treatment for alcohol use disorder, with the ensuing risk of returning to alcohol use. CONCLUSIONS: While early liver transplantation for AH has survival benefits, many patients would not have received treatment for alcohol use disorder. An integrated approach to evaluating candidacy for early liver transplantation is needed.

Epidemic within a pandemic: Alcohol-associated hepatitis and COVID-19.

BACKGROUND: There was an increase in alcoholic beverage sales during the peak of the COVID pandemic in the United States. However, little is known about the impact of SARS-CoV-2 infection among hospitalized alcohol-associated hepatitis (AH) patients. METHODS: We analyzed the available National Inpatient Data (NIS) data from 2020 to determine mortality and healthcare utilization among hospitalized AH patients with and without COVID-19 in the United States. RESULTS: We observed a ~15.6% increase in cases of hospitalized AH patients from 136,620 in 2019 to 157,885 in 2020, a significant increase from an average of 5.5% per annum despite an 8.7% decline in US hospital admissions over the same time span. Men younger than 40 were the fastest growing AH group, with a 23% increase in 2020. Approximately 1.8% of hospitalized AH patients had a SARS-CoV-2 infection, which significantly worsened the mortality among patients with AH (11.4% vs. 4.1%, p < 0.0001). This was especially true among older AH patients with concomitant conditions such as clinically apparent cirrhosis, acute renal failure, upper gastrointestinal bleeding, and sepsis. AH patients with COVID-19 also had a longer length of stay (8.6 vs. 6.1 days, p < 0.0001) and higher hospital charges during the stay ($93,670 vs. $66,283, p < 0.0001) than those without COVID-19. CONCLUSION: Our study highlights the rise in AH cases during the COVID-19 pandemic. Screening and appropriate management of excessive alcohol use and preventive measures such as COVID-19 vaccination should be considered to reduce morbidity and mortality among patients with AH.

Prevalence and clinical impact of alcohol withdrawal syndrome in alcohol-associated hepatitis and the potential role of prophylaxis: a multinational, retrospective cohort study.

Background: The prevalence and impact of alcohol withdrawal syndrome (AWS) in patients with alcohol-associated hepatitis (AH) are unknown. In this study, we aimed to investigate the prevalence, predictors, management, and clinical impact of AWS in patients hospitalized with AH. Methods: A multinational, retrospective cohort study enrolling patients hospitalized with AH at 5 medical centres in Spain and in the USA was performed between January 1st, 2016 to January 31st, 2021. Data were retrospectively retrieved from electronic health records. Diagnosis of AWS was based on clinical criteria and use of sedatives to control AWS symptoms. The primary outcome was mortality. Multivariable models controlling for demographic variables and disease severity were performed to determine predictors of AWS (adjusted odds ratio [OR]) and the impact of AWS condition and management on clinical outcomes (adjusted hazard ratio [HR]). Findings: In total, 432 patients were included. The median MELD score at admission was 21.9 (18.3-27.3). The overall prevalence of AWS was 32%. Lower platelet levels (OR = 1.61, 95% CI 1.05-2.48) and previous history of AWS (OR = 2.09, 95% CI 1.31-3.33) were associated with a higher rate of incident AWS, whereas the use of prophylaxis decreased the risk (OR = 0.58, 95% CI 0.36-0.93). The use of intravenous benzodiazepines (HR = 2.18, 95% CI 1.02-4.64) and phenobarbital (HR = 2.99, 95% CI 1.07-8.37) for AWS treatment were independently associated with a higher mortality. The development of AWS increased the rate of infections (OR = 2.24, 95% CI 1.44-3.49), the need for mechanical ventilation (OR = 2.49, 95% CI 1.38-4.49), and ICU admission (OR = 1.96, 95% CI 1.19-3.23). Finally, AWS was associated with higher 28-day (HR = 2.31, 95% CI 1.40-3.82), 90-day (HR = 1.78, 95% CI 1.18-2.69), and 180-day mortality (HR = 1.54, 95% CI 1.06-2.24). Interpretation: AWS commonly occurs in patients hospitalized with AH and complicates the hospitalization course. Routine prophylaxis is associated with a lower prevalence of AWS. Prospective studies should determine diagnostic criteria and prophylaxis regimens for AWS management in patients with AH. Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.