Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease.

Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality1-3. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice4, but little is known about the microbial factors that are responsible for this process. Here we identify cytolysin-a two-subunit exotoxin that is secreted by Enterococcus faecalis5,6-as a cause of hepatocyte death and liver injury. Compared with non-alcoholic individuals or patients with alcohol-use disorder, patients with alcoholic hepatitis have increased faecal numbers of E. faecalis. The presence of cytolysin-positive (cytolytic) E. faecalis correlated with the severity of liver disease and with mortality in patients with alcoholic hepatitis. Using humanized mice that were colonized with bacteria from the faeces of patients with alcoholic hepatitis, we investigated the therapeutic effects of bacteriophages that target cytolytic E. faecalis. We found that these bacteriophages decrease cytolysin in the liver and abolish ethanol-induced liver disease in humanized mice. Our findings link cytolytic E. faecalis with more severe clinical outcomes and increased mortality in patients with alcoholic hepatitis. We show that bacteriophages can specifically target cytolytic E. faecalis, which provides a method for precisely editing the intestinal microbiota. A clinical trial with a larger cohort is required to validate the relevance of our findings in humans, and to test whether this therapeutic approach is effective for patients with alcoholic hepatitis.

ACG Clinical Guideline: Alcohol-Associated Liver Disease.

ABSTRACT: Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful alcohol use as the primary risk factor, increasing alcohol use over the past decade has resulted in rapid growth of the ALD-related healthcare burden. The spectrum of ALD ranges from early asymptomatic liver injury to advanced disease with decompensation and portal hypertension. Compared with those with other etiologies of liver disease, patients with ALD progress faster and more often present at an advanced stage. A unique phenotype of advanced disease is alcohol-associated hepatitis (AH) presenting with rapid onset or worsening of jaundice, and acute on chronic liver failure in severe forms conveying a 1-month mortality risk of 20%-50%. The model for end stage disease score is the most accurate score to stratify AH severity (>20 defined as severe disease). Corticosteroids are currently the only available therapeutic with proven efficacy for patients with severe AH, providing survival benefit at 1 month in 50%-60% of patients. Abstinence of alcohol use, a crucial determinant of long-term outcomes, is challenging to achieve in ALD patients with concurrent alcohol use disorder (AUD). As patients with ALD are rarely treated for AUD, strategies are needed to overcome barriers to AUD treatment in patients with ALD and to promote a multidisciplinary integrated care model with hepatology, addiction medicine providers, and social workers to comprehensively manage the dual pathologies of liver disease and of AUD. Liver transplantation, a definitive treatment option in patients with advanced cirrhosis, should be considered in selected patients with AH, who are unresponsive to medical therapy and have a low risk of relapse to posttransplant alcohol use. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the American College of Gastroenterology Practice Parameters Committee.

Transfusion-associated acute lung injury following albumin treatment in liver disease.

BACKGROUND AND OBJECTIVES: Transfusion-related acute lung injury is an infrequent adverse reaction observed in patients receiving blood products. The lung injury can range in severity and can be associated with both mortality and mortality. All blood products except albumin have been linked to cases of transfusion-related acute lung injury. In fact, albumin may be used as a salvage modality in severe transfusion-related acute lung injury. We report an alcoholic patient who developed lung injury following treatment with albumin in the setting of hypoalbuminaemia. MATERIALS AND METHODS: A 41-year-old male with alcoholic liver disease was admitted for severe ascites and alcoholic hepatitis. Chest x-ray showed small pleural effusions at the lung bases with no overt pulmonary oedema. He received high doses of furosemide for lower extremity oedema. The patient received a total of two albumin infusions to augment the diuresis effect. RESULTS: He subsequently developed acute hypoxic respiratory failure with imaging showing interstitial and airspace abnormalities concerning for pulmonary oedema. He showed no additional signs of volume overload and was treated supportively until the condition improved. CONCLUSION: This is the first reported case of albumin-associated lung injury proximally related to albumin infusion. We aim to increase awareness of this possible sequelae among physicians.

Racial Disparities in Alcoholic Hepatitis Hospitalizations in the United States: Trends, Outcomes, and Future Projections.

INTRODUCTION: Alcoholic hepatitis (AH) is a serious complication of alcohol consumption with high morbidity and mortality, particularly in the United States where alcohol-related liver diseases rank as one of the leading causes of preventable death. Our study aims to analyze the morbidity and mortality of AH across racial groups and project hospitalization trends up to 2028, thereby informing public health initiatives. METHODS: We conducted a cross-sectional study utilizing data from the Nationwide Inpatient Sample (NIS) spanning 2012 to 2021. The study population comprised hospitalizations identified using specific ICD-9-CM and ICD-10-CM codes for AH. We assessed hospitalizations, in-hospital mortality rates, length of stay (LOS), and morbidities related to alcoholic hepatitis adjusting for sociodemographic factors and hospital characteristics. Statistical analyses were performed using Stata and R software, employing logistic and linear regression analyses, and SARIMA models for forecasting. RESULTS: Our results indicated a predominantly White cohort (68%), with a notable increase in AH hospitalizations among Hispanics (129.1% from 2012 to 2021). Racial disparities were observed in inpatient mortality, liver transplant accessibility, and the occurrence of in-hospital complications. The study forecasts a continued rise in hospitalizations across all racial groups, with Hispanics experiencing the sharpest increase. CONCLUSION: Our study reveals a disproportionate rise in the AH burden among Hispanics with projections indicating a persistent upward trend through 2028. These findings highlight the need for targeted public health strategies and improved healthcare access to mitigate the increasing AH burden and address disparities in care and outcomes.

An update on treatment and outcomes for alcoholic hepatitis.

ABSTRACT: Alcoholic hepatitis is a form of inflammation of the liver caused by alcohol use. Data on the best treatment are conflicting. Treatment guidelines include the use of prednisolone and supportive care, although this is controversial. This article reviews the guidelines for treating alcoholic hepatitis and current recommendations.

EASL Clinical Practice Guidelines on acute-on-chronic liver failure.

Acute-on-chronic liver failure (ACLF), which was described relatively recently (2013), is a severe form of acutely decompensated cirrhosis characterised by the existence of organ system failure(s) and a high risk of short-term mortality. ACLF is caused by an excessive systemic inflammatory response triggered by precipitants that are clinically apparent (e.g., proven microbial infection with sepsis, severe alcohol-related hepatitis) or not. Since the description of ACLF, some important studies have suggested that patients with ACLF may benefit from liver transplantation and because of this, should be urgently stabilised for transplantation by receiving appropriate treatment of identified precipitants, and full general management, including support of organ systems in the intensive care unit (ICU). The objective of the present Clinical Practice Guidelines is to provide recommendations to help clinicians recognise ACLF, make triage decisions (ICU vs. no ICU), identify and manage acute precipitants, identify organ systems that require support or replacement, define potential criteria for futility of intensive care, and identify potential indications for liver transplantation. Based on an in-depth review of the relevant literature, we provide recommendations to navigate clinical dilemmas followed by supporting text. The recommendations are graded according to the Oxford Centre for Evidence-Based Medicine system and categorised as 'weak' or 'strong'. We aim to provide the best available evidence to aid the clinical decision-making process in the management of patients with ACLF.

The Beneficial Effects of Lactobacillus GG Therapy on Liver and Drinking Assessments in Patients with Moderate Alcohol-Associated Hepatitis.

INTRODUCTION: We investigated the effect of daily oral Lactobacillus rhamnosus GG (LGG) in reducing liver injury/severity and drinking in patients with alcohol use disorder and moderately severe alcohol-associated hepatitis. METHODS: Forty-six male and female individuals with alcohol use disorder and moderate alcohol-associated hepatitis (12 ≤ model for end-stage liver disease score < 20, aged 21-67 years) received either LGG (n = 24) or placebo (n = 22). Data were collected/assessed at baseline and at 1, 3, and 6 months. RESULTS: LGG treatment was associated with a significant reduction in liver injury after 1 month. Six months of LGG treatment reduced heavy drinking levels to social or abstinence levels. DISCUSSION: LGG treatment was associated with an improvement in both liver injury and drinking.

Recovery and outcomes of patients denied early liver transplantation for severe alcohol-associated hepatitis.

BACKGROUND AND AIMS: Liver transplantation (LT) in alcohol-associated hepatitis (AH) remains controversial, in part because spontaneous recovery (SR) can occur. There is a paucity of data on SR in patients with severe AH who undergo LT evaluation. The purpose of this study was to determine factors associated with SR and survival in patients with severe AH who undergo LT evaluation. APPROACH AND RESULTS: This is a retrospective study of ALD patients with Model for End-Stage Liver Disease (MELD) >25 and <90 days abstinence who underwent LT evaluation at a single center between 2012 and 2018. One hundred forty-four patients (median age, 45.5 years; 68.1% male) were included. Forty-nine (34%) underwent LT and 95 (66%) patients did not undergo LT, and of those, 34 (23.6%) experienced SR. Factors associated with recovery were younger age (OR, 0.92; p = 0.004), lower index international normalized ratio (INR; 0.31; p = 0.03), and lower peak MELD (OR, 0.83; p = 0.02). Only 7 patients (20.6%) achieved a compensated state with a MELD <15 and absence of therapy for ascites or HE. Survival was improved in patients who underwent early LT when compared to SR. Survival was impaired in SR following relapse to alcohol use when compared to SR patients who abstained and LT recipients. Among all 6-month survivors of AH, alcohol use trended toward an association with mortality (HR, 2.05; p = 0.17), but only LT was associated with decreased mortality risk (HR, 0.20; p = 0.005). CONCLUSIONS: SR from AH after LT evaluation is associated with age, index INR, and lower peak MELD. Most recovered patients continue to experience end-stage complications. LT is the only factor associated with lower mortality.

Management of alcoholic hepatitis: A clinical perspective.

Alcohol-associated liver disease is the primary cause of liver-related mortality worldwide and one of the most common indications for liver transplantation. Alcoholic hepatitis represents the most acute and severe manifestation of alcohol-associated liver disease and is characterized by a rapid onset of jaundice with progressive inflammatory liver injury, worsening of portal hypertension, and an increased risk for multiorgan failure in patients with excessive alcohol consumption. Severe alcoholic hepatitis is associated with a poor prognosis and high short-term mortality. During the COVID-19 pandemic, rates of alcohol-associated hepatitis have increased significantly, underscoring that it is a serious and growing health problem. However, adequate management of alcohol-associated hepatitis and its complications in everyday clinical practice remains a major challenge. Currently, pharmacotherapy is limited to corticosteroids, although these have only a moderate effect on reducing short-term mortality. In recent years, translational studies deciphering key mechanisms of disease development and progression have led to important advances in the understanding of the pathogenesis of alcoholic hepatitis. Emerging pathophysiology-based therapeutic approaches include anti-inflammatory agents, modifications of the gut-liver axis and intestinal dysbiosis, epigenetic modulation, antioxidants, and drugs targeting liver regeneration. Concurrently, evidence is increasing that early liver transplantation is a safe treatment option with important survival benefits in selected patients with severe alcoholic hepatitis not responding to medical treatment. This narrative review describes current pathophysiology and management concepts of alcoholic hepatitis, provides an update on emerging treatment options, and focuses on the need for holistic and patient-centred treatment approaches to improve prognosis.

Current and future treatment for alcoholic-related liver diseases.

The socioeconomic burden of alcohol-related liver disease has been increasing worldwide. Its prevalence is underestimated, and patients with alcohol-related liver disease are rarely diagnosed in the earlier phase of the disease spectrum. Alcoholic hepatitis is a distinct syndrome with life-threatening signs of systemic inflammation. In severe alcoholic hepatitis, prednisolone is indicated as the first-line treatment even with the possibility of various complications. Early liver transplantation can be another option for highly selected patients with a null response to prednisolone. Most importantly, abstinence is the mainstay of long-term care, but relapse is frequent among patients. Recent findings on the pathogenesis of alcoholic hepatitis have enabled us to discover new therapeutic targets. Preventing hepatic inflammation, reducing oxidative stress, improving gut dysbiosis, and enhancing liver regeneration are the main targets of emerging therapies. Herein, we review the pathogenesis, current treatment, and barriers to successful clinical trials of alcoholic hepatitis. Additionally, clinical trials for alcoholic hepatitis, either ongoing or recently completed, will be briefly introduced.

Intestinal Microbiotas and Alcoholic Hepatitis: Pathogenesis and Therapeutic Value.

Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several underlying mechanisms that contribute to the development of AH, including metabolic alterations, immune stimulation, and intestinal dysbiosis. These pathological changes intricately intertwine during the progression of AH. Notably, recent studies have increasingly highlighted the pivotal role of alterations in the intestinal microbiota in the pathogenesis of AH. Consequently, future investigations should place significant emphasis on exploring the dynamics of intestinal microbiota. In this comprehensive review, we consolidate the primary causes of AH while underscoring the influence of gut microbes. Furthermore, by examining AH treatment strategies, we delineate the potential therapeutic value of interventions targeting the gut microbiota. Given the existing limitations in AH treatment options, we anticipate that this review will contribute to forthcoming research endeavors aimed at advancing AH treatment modalities.

[A case of severe alcoholic hepatitis successfully treated with granulocytapheresis].

A 46-year-old male patient with a drinking history presented at our hospital with jaundice. He was diagnosed with moderate alcoholic hepatitis based on laboratory data. The white blood cell (WBC) counts were gradually increased and the prothrombin time was prolonged after hospitalization. Methylprednisolone (1000mg/day for 3 days) followed by oral prednisolone (40mg/day) was administered. However, the liver function was not improved and the patient progressed to severe alcoholic hepatitis. Therefore, we performed granulocytapheresis (GCAP). The WBC counts and interleukin-6 decreased and the liver function improved after 3 GCAP sessions.

Therapeutic advances in alcohol-associated hepatitis.

In recent years, there have been important advances in our understanding of alcohol-associated hepatitis (AH), which have occurred in parallel with a surge in clinical trial activity. Meanwhile, the broader medical field has seen a transformation in care paradigms based on emerging digital technologies. This review focuses on breakthroughs in our understanding of AH and how these breakthroughs are leading to new paradigms for biomarker discovery, clinical trial activity, and care models for patients. It portends a future in which multimodal data from genetic, radiomic, histologic, and environmental sources can be integrated and synthesised to generate personalised biomarkers and therapies for patients with AH.

Alcoholic Hepatitis: Diagnosis and Management.

Alcoholic hepatitis is a clinical syndrome characterized by acute-onset jaundice and liver enzyme abnormalities in the setting of long-term heavy alcohol use. High rates of concomitant infections, systemic inflammation, and multiorgan failure lead to significant morbidity and mortality. Diagnosis of alcoholic hepatitis is primarily clinical, based on a consensus definition from the National Institute on Alcohol Abuse and Alcoholism. Initial workup should include chest radiography and cultures of peritoneal fluid, blood, and urine. Close monitoring for inflammation and organ failure is crucial throughout hospitalization. Laboratory-based prognostic scores, including Maddrey Discriminant Function and the Model for End-Stage Liver Disease, help determine disease severity and treatment options. Treatment for moderate disease primarily consists of supportive care, including alcohol cessation and nutritional support. Corticosteroids are recommended for severe alcoholic hepatitis. Responsiveness to corticosteroid therapy should be evaluated using the Lille score on day 7 of treatment. Hospital physicians should involve a multidisciplinary team, including substance abuse specialists, gastroenterologists or hepatologists, nephrologists, dietitians, and intensivists, as appropriate. Long-term follow-up should focus on abstinence from alcohol, management of underlying cirrhosis, and evaluation for liver transplantation if indicated. Pharmacologic treatment of alcohol use disorder can aid patients in maintaining abstinence from alcohol. The presence of underlying cirrhosis and continued alcohol use negatively impact long-term prognosis.

Severe alcoholic hepatitis as precipitant for organ failure and ACLF.

Alcoholic hepatitis is the acute deterioration of alcoholic liver disease with rapid onset or worsening of jaundice, which in severe cases, may transition to acute-on-chronic liver failure with extremely high short-term mortality, increasing with the number and severity of hepatic and extra-hepatic organ dysfunction. Diagnosis and treatment are insufficient and challenging, especially due to the complex, multi-factorial and as yet not fully understood pathogenesis. While current management is limited to steroids and best supportive care, debate is ongoing concerning liver transplantation for selected patients, and several novel approaches are under way with mixed results. These drawbacks in disease management together with increasing prevalence in Germany, and generally in Western countries, constitute an unmet need for the healthcare systems. This review tries to summarize the current status of these aspects and provides an overview for pathogenesis, management and potential future treatments.

Fecal microbiota transplant, its usefulness beyond Clostridioides difficile in gastrointestinal diseases.

Fecal microbiota transplant (FMT) is currently recommended for recurrent Clostridioidesdifficile infection. However, it is interesting to acknowledge the potential therapeutic role in other diseases associated with dysbiosis. This review will focus on the current and potential indications of FMT in gastrointestinal diseases, evaluating the available evidence and also exposing the necessary requirements to carry it out.

[Progress in the clinical treatment of alcoholic hepatitis].

Alcoholic hepatitis is a severe and life-threatening systemic inflammatory response syndrome, which has a high incidence and mortality rate worldwide. The severity ranges from asymptomatic liver biochemical disturbances to fulminant liver failure or death; however, there are few effective therapeutic interventions. Maddrey discriminant function not only predicts short-term mortality, but it also guides clinicians to choose appropriate alcoholic hepatitis-specific treatments. Alcohol abstinence, nutritional support, psychological counseling, and infection prevention remain the cornerstones for alcoholic hepatitis treatment. Corticosteroids remain the mainstay of treatment when patients have a good appetite and normal serum creatinine levels, but early liver transplantation is the only life-saving option for steroid-unresponsive patients. New studies have found that gut microbiota is an important therapeutic targets in patients with alcohol hepatitis, and N-acetylcysteine, granulocyte colony-stimulating factor, and metadoxine as adjunctive therapy have a positive effect on patient survival.

Early liver transplantation for acute alcoholic hepatitis: We can't say no.

In patients with severe alcoholic hepatitis who are not responding to medical therapy, it is detrimental to postpone the decision to list a patient as there are no therapeutic alternatives. Early transplantation of patients with severe alcoholic hepatitis, using a restrictive selection process, has increasingly been used in the last decade with acceptable relapse rates. Indeed, early transplantation has gained the support of a growing number of experts from different countries, as shown by the European, American and Latin American recommendations. However, there is still great heterogeneity in its application between countries and even between centres within the same country.

Intestinal Virome in Patients With Alcoholic Hepatitis.

BACKGROUND AND AIMS: Alcoholic hepatitis (AH) is a severe manifestation of alcohol-associated liver disease (ALD) with high mortality. Although gut bacteria and fungi modulate disease severity, little is known about the effects of the viral microbiome (virome) in patients with ALD. APPROACH AND RESULTS: We extracted virus-like particles from 89 patients with AH who were enrolled in a multicenter observational study, 36 with alcohol use disorder (AUD), and 17 persons without AUD (controls). Virus-like particles from fecal samples were fractionated using differential filtration techniques, and metagenomic sequencing was performed to characterize intestinal viromes. We observed an increased viral diversity in fecal samples from patients with ALD, with the most significant changes in samples from patients with AH. Escherichia-, Enterobacteria-, and Enterococcus phages were over-represented in fecal samples from patients with AH, along with significant increases in mammalian viruses such as Parvoviridae and Herpesviridae. Antibiotic treatment was associated with higher viral diversity. Specific viral taxa, such as Staphylococcus phages and Herpesviridae, were associated with increased disease severity, indicated by a higher median Model for End-Stage Liver Disease score, and associated with increased 90-day mortality. CONCLUSIONS: In conclusion, intestinal viral taxa are altered in fecal samples from patients with AH and associated with disease severity and mortality. Our study describes an intestinal virome signature associated with AH.

The Changing Burden of Alcoholic Hepatitis: Rising Incidence and Associations with Age, Gender, Race, and Geography.

Alcoholic hepatitis is a major cause of morbidity and mortality. However, there are limited population-based data on its incidence, demographics, and temporal trends. We performed a retrospective cohort study using the State Inpatient Databases from Florida, Massachusetts, New York, and Washington from 2010 to 2014. We included patients aged 20-79 years admitted with alcoholic hepatitis and calculated incidence using population denominators obtained from the Centers for Disease Control and Prevention WONDER database. We fit multivariable Poisson regression models to explore interactions between alcoholic hepatitis incidence rates and several predictors including state, calendar year, age, race/ethnicity, and gender. Among 56,973 unique individuals with alcoholic hepatitis, the majority were male (39,702; 69.7%) and white non-Hispanic (40,934; 72.0%). In multivariable Poisson models, there was a significant interaction between calendar year and age group (p < 0.001), with the highest incidence rates in those ages 40-49 and 50-59 across all years. The absolute increase in incidence rate across calendar years was highest in the 20-29 and 30-39 age groups in every state. Female gender was associated with a lower rate (incidence rate ratio (IRR) 0.42, 95% confidence interval (CI) 0.41-0.42, p < 0.001). Compared to white non-Hispanics, black non-Hispanics (IRR 0.79, CI 0.77-0.81, p < 0.001) and Hispanics (0.66, CI 0.65-0.68, p < 0.001) had lower incidence rates. The incidence of alcoholic hepatitis in the USA varies by age, gender, race/ethnicity, and state of residence. The group with the fastest rising incidence is those aged 20-39. More work is needed to evaluate the reasons for the temporal trends for admissions for alcoholic hepatitis.