-
Alcohol and Alcoholism (Oxford,... Jul 2019Alcoholic liver disease (ALD) represents a spectrum of injury, ranging from simple steatosis to alcoholic hepatitis to cirrhosis. Regular alcohol use results in fatty... (Review)
Review
Alcoholic liver disease (ALD) represents a spectrum of injury, ranging from simple steatosis to alcoholic hepatitis to cirrhosis. Regular alcohol use results in fatty changes in the liver which can develop into inflammation, fibrosis and ultimately cirrhosis with continued, excessive drinking. Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality that can occur in patients with steatosis or underlying cirrhosis. The pathogenesis of ALD is multifactorial and in addition to genetic factors, alcohol-induced hepatocyte damage, reactive oxygen species, gut-derived microbial components result in steatosis and inflammatory cell (macrophage and neutrophil leukocyte) recruitment and activation in the liver. Continued alcohol and pro-inflammatory cytokines induce stellate cell activation and result in progressive fibrosis. Other than cessation of alcohol use, medical therapy of AH is limited to prednisolone in a subset of patients. Given the high mortality of AH and the progressive nature of ALD, there is a major need for new therapeutic intervention for this underserved patient population.
Topics: Hepatitis, Alcoholic; Humans; Inflammation Mediators; Kupffer Cells; Reactive Oxygen Species
PubMed: 31219169
DOI: 10.1093/alcalc/agz036 -
The Lancet. Gastroenterology &... May 2020Alcoholic hepatitis is an acute, inflammatory liver disease associated with high morbidity and mortality both in the short term and long term. Alcoholic hepatitis often... (Review)
Review
Alcoholic hepatitis is an acute, inflammatory liver disease associated with high morbidity and mortality both in the short term and long term. Alcoholic hepatitis often arises in patients with a background of chronic liver disease and it is characterised by the rapid onset of jaundice and the development of myriad complications. Medical therapy for severe alcoholic hepatitis relies on corticosteroids, which have modest effectiveness. Abstinence from alcohol is critically important in patients with alcoholic hepatitis, but recidivism is high. Because of the absence of effective medical treatments for alcoholic hepatitis and alcohol dependency, there is a pressing need to develop new and effective therapeutics. Supported by promising preliminary and preclinical studies, many ongoing clinical trials of new therapies for alcoholic hepatitis are currently underway and are discussed further in this Series paper.
Topics: Adrenal Cortex Hormones; Alcohol Abstinence; Alcoholism; Anti-Bacterial Agents; Anti-Inflammatory Agents; Antioxidants; Dietary Supplements; Hepatitis, Alcoholic; Humans; Pentanoic Acids; Probiotics; Receptors, Interleukin-1; Signal Transduction; Tumor Necrosis Factor-alpha
PubMed: 32277902
DOI: 10.1016/S2468-1253(19)30326-7 -
Clinics in Liver Disease Feb 2019Alcoholic hepatitis is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by prolonged heavy alcohol use. Treatment is... (Review)
Review
Alcoholic hepatitis is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by prolonged heavy alcohol use. Treatment is mostly supportive. The short-term prognosis of acute alcoholic hepatitis depends on liver recovery, and ranges widely from rapid improvement to grim multiorgan failure despite treatment. Refinement of scoring systems have enhanced prognostication to guide clinical decision making in alcoholic hepatitis. Recent advances in the treatment of alcoholic hepatitis have solidified corticosteroids as the cornerstone of treatment to enhance short-term survival, but not intermediate or long-term survival.
Topics: Acute Disease; Alanine Transaminase; Aspartate Aminotransferases; Biopsy; Elasticity Imaging Techniques; Glucocorticoids; Hepatitis, Alcoholic; Humans; Jaundice; Liver; Prednisolone; Prognosis; Severity of Illness Index
PubMed: 30454835
DOI: 10.1016/j.cld.2018.09.005 -
The American Journal of Gastroenterology Feb 2018Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most...
Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.
Topics: Alcohol Withdrawal Delirium; Alcoholism; Hepatitis, Alcoholic; Humans; Liver Diseases, Alcoholic; Liver Transplantation; Prognosis
PubMed: 29336434
DOI: 10.1038/ajg.2017.469 -
Journal of Hepatology Aug 2023Acute-on-chronic liver failure (ACLF), which was described relatively recently (2013), is a severe form of acutely decompensated cirrhosis characterised by the existence...
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.
Topics: Humans; Acute-On-Chronic Liver Failure; Prognosis; Liver Transplantation; Medical Futility; Intensive Care Units; Hepatitis, Alcoholic; Liver Cirrhosis
PubMed: 37364789
DOI: 10.1016/j.jhep.2023.04.021 -
The New England Journal of Medicine Dec 2022
Review
Topics: Humans; Alcohol Drinking; Hepatitis; Liver Cirrhosis; Hepatitis, Alcoholic
PubMed: 36577100
DOI: 10.1056/NEJMra2207599 -
Nature Nov 2019Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality. Alcoholic hepatitis is a severe and...
Chronic liver disease due to alcohol-use disorder contributes markedly to the global burden of disease and mortality. Alcoholic hepatitis is a severe and life-threatening form of alcohol-associated liver disease. The gut microbiota promotes ethanol-induced liver disease in mice, 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 faecalis-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.
Topics: Alcoholism; Animals; Bacteriophages; Enterococcus faecalis; Ethanol; Fatty Liver; Feces; Female; Gastrointestinal Microbiome; Germ-Free Life; Hepatitis, Alcoholic; Hepatocytes; Humans; Liver; Male; Mice; Mice, Inbred C57BL; Perforin; Phage Therapy
PubMed: 31723265
DOI: 10.1038/s41586-019-1742-x -
World Journal of Gastroenterology May 2023Alcohol-related hepatitis (ARH) is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by significant alcohol use. It... (Review)
Review
Alcohol-related hepatitis (ARH) is a unique type of alcohol-associated liver disease characterized by acute liver inflammation caused by significant alcohol use. It ranges in severity from mild to severe and carries significant morbidity and mortality. The refinement of scoring systems has enhanced prognostication and guidance of clinical decision-making in the treatment of this complex disease. Although treatment focuses on supportive care, steroids have shown benefit in select circumstances. There has been a recent interest in this disease process, as coronavirus disease 2019 pandemic led to substantial rise in cases. Although much is known regarding the pathogenesis, prognosis remains grim due to limited treatment options. This article summarizes the epidemiology, genetics, pathogenesis, diagnosis and treatment of ARH.
Topics: Humans; COVID-19; Hepatitis, Alcoholic; Prognosis; Liver Diseases, Alcoholic; Steroids
PubMed: 37213401
DOI: 10.3748/wjg.v29.i17.2551 -
Clinics in Liver Disease Aug 2021
Topics: Hepatitis, Alcoholic; Humans
PubMed: 34229847
DOI: 10.1016/j.cld.2021.04.003 -
The Journal of Clinical Investigation Jul 2022Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in...
Intrahepatic neutrophil infiltration has been implicated in severe alcoholic hepatitis (SAH) pathogenesis; however, the mechanism underlying neutrophil-induced injury in SAH remains obscure. This translational study aims to describe the patterns of intrahepatic neutrophil infiltration and its involvement in SAH pathogenesis. Immunohistochemistry analyses of explanted livers identified two SAH phenotypes despite a similar clinical presentation, one with high intrahepatic neutrophils (Neuhi), but low levels of CD8+ T cells, and vice versa. RNA-Seq analyses demonstrated that neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with hepatic inflammation and disease progression. To study specifically the mechanisms related to Neuhi in AH patients and liver injury, we used the mouse model of chronic-plus-binge ethanol feeding and found that myeloid-specific deletion of the Ncf1 gene abolished ethanol-induced hepatic inflammation and steatosis. RNA-Seq analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic hepatitis (AH) by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key antiinflammatory and antifibrotic microRNA). In conclusion, two distinct histopathological phenotypes based on liver immune phenotyping are observed in SAH patients, suggesting a separate mechanism driving liver injury and/or failure in these patients.
Topics: Animals; Ethanol; Hepatitis, Alcoholic; Inflammation; Liver; Liver Diseases, Alcoholic; Mice; Mice, Inbred C57BL; Phenotype; Reactive Oxygen Species
PubMed: 35838051
DOI: 10.1172/JCI157780