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Journal of Hepatology Mar 2020Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the... (Clinical Trial)
Clinical Trial
BACKGROUND & AIMS
Alcohol-associated liver disease is a leading indication for liver transplantation and a leading cause of mortality. Alterations to the gut microbiota contribute to the pathogenesis of alcohol-associated liver disease. Patients with alcohol-associated liver disease have increased proportions of Candida spp. in the fecal mycobiome, yet little is known about the effect of intestinal Candida on the disease. Herein, we evaluated the contributions of Candida albicans and its exotoxin candidalysin in alcohol-associated liver disease.
METHODS
C. albicans and the extent of cell elongation 1 (ECE1) were analyzed in fecal samples from controls, patients with alcohol use disorder and those with alcoholic hepatitis. Mice colonized with different and genetically manipulated C. albicans strains were subjected to the chronic-plus-binge ethanol diet model. Primary hepatocytes were isolated and incubated with candidalysin.
RESULTS
The percentages of individuals carrying ECE1 were 0%, 4.76% and 30.77% in non-alcoholic controls, patients with alcohol use disorder and patients with alcoholic hepatitis, respectively. Candidalysin exacerbates ethanol-induced liver disease and is associated with increased mortality in mice. Candidalysin enhances ethanol-induced liver disease independently of the β-glucan receptor C-type lectin domain family 7 member A (CLEC7A) on bone marrow-derived cells, and candidalysin does not alter gut barrier function. Candidalysin can damage primary hepatocytes in a dose-dependent manner in vitro and is associated with liver disease severity and mortality in patients with alcoholic hepatitis.
CONCLUSIONS
Candidalysin is associated with the progression of ethanol-induced liver disease in preclinical models and worse clinical outcomes in patients with alcoholic hepatitis.
LAY SUMMARY
Candidalysin is a peptide toxin secreted by the commensal gut fungus Candida albicans. Candidalysin enhances alcohol-associated liver disease independently of the β-glucan receptor CLEC7A on bone marrow-derived cells in mice without affecting intestinal permeability. Candidalysin is cytotoxic to primary hepatocytes, indicating a direct role of candidalysin on ethanol-induced liver disease. Candidalysin might be an effective target for therapy in patients with alcohol-associated liver disease.
Topics: Adult; Aged; Animals; Candida albicans; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Exotoxins; Feces; Female; Fungal Proteins; Gastrointestinal Microbiome; Hepatitis, Alcoholic; Hepatocytes; Humans; Lectins, C-Type; Liver Diseases, Alcoholic; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Severity of Illness Index
PubMed: 31606552
DOI: 10.1016/j.jhep.2019.09.029 -
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 -
The American Journal of Gastroenterology Jan 2024Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful...
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.
Topics: Humans; Liver Diseases, Alcoholic; Risk Factors; Hepatitis, Alcoholic; Liver Cirrhosis; Alcoholism
PubMed: 38174913
DOI: 10.14309/ajg.0000000000002572 -
Gastroenterology Apr 2016
Topics: Clinical Trials as Topic; Consensus; Endpoint Determination; Hepatitis, Alcoholic; Humans; Research Design; Risk Factors; Severity of Illness Index; Terminology as Topic; Time Factors; Treatment Outcome
PubMed: 26921783
DOI: 10.1053/j.gastro.2016.02.042 -
Frontiers in Immunology 2023Alcoholic hepatitis (AH) is a major health problem worldwide. There is increasing evidence that immune cells, iron metabolism and copper metabolism play important roles...
BACKGROUNDS
Alcoholic hepatitis (AH) is a major health problem worldwide. There is increasing evidence that immune cells, iron metabolism and copper metabolism play important roles in the development of AH. We aimed to explore biomarkers that are co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients.
METHODS
GSE28619 and GSE103580 datasets were integrated, CIBERSORT algorithm was used to analyze the infiltration of 22 types of immune cells and GSVA algorithm was used to calculate ferroptosis and cuproptosis scores. Using the "WGCNA" R package, we established a gene co-expression network and analyzed the correlation between M1 macrophages, ferroptosis and cuproptosis scores and module characteristic genes. Subsequently, candidate genes were screened by WGCNA and differential expression gene analysis. The LASSO-SVM analysis was used to identify biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis. Finally, we validated these potential biomarkers using GEO datasets (GSE155907, GSE142530 and GSE97234) and a mouse model of AH.
RESULTS
The infiltration level of M1 macrophages was significantly increased in AH patients. Ferroptosis and cuproptosis scores were also increased in AH patients. In addition, M1 macrophages, ferroptosis and cuproptosis were positively correlated with each other. Combining bioinformatics analysis with a mouse model of AH, we found that ALDOA, COL3A1, LUM, THBS2 and TIMP1 may be potential biomarkers co-associated with M1 macrophages, ferroptosis and cuproptosis in AH patients.
CONCLUSION
We identified 5 potential biomarkers that are promising new targets for the treatment and diagnosis of AH patients.
Topics: Animals; Mice; Biomarkers; Computational Biology; Disease Models, Animal; Ferroptosis; Hepatitis, Alcoholic; Macrophages; Copper; Apoptosis
PubMed: 37090703
DOI: 10.3389/fimmu.2023.1146693 -
Clinics in Liver Disease Aug 2021The natural history of moderate alcoholic hepatitis (AH) is not well known. It is a frequent disease with a probable underestimated incidence compared with its severe... (Review)
Review
The natural history of moderate alcoholic hepatitis (AH) is not well known. It is a frequent disease with a probable underestimated incidence compared with its severe form. Among the different prognostic scores predicting short-term mortality in AH, MELD seems to be the most accurate. The mortality of moderate AH is 3% to 7% in the short to medium term and 13% to 20% at 1 year, mainly because of liver-related complications, including severe infections. Long-term abstinence is the main goal of the treatment. There is still need for the development of new therapies for AH, including the less severe forms.
Topics: Hepatitis, Alcoholic; Humans; Incidence
PubMed: 34229838
DOI: 10.1016/j.cld.2021.03.001 -
Journal of Hepatology Oct 2021Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study...
BACKGROUND & AIMS
Alcoholic hepatitis (AH) is a life-threatening disease with limited therapeutic options, as the molecular mechanisms leading to death are not well understood. This study evaluates the Hippo/Yes-associated protein (YAP) pathway which has been shown to play a role in liver regeneration.
METHOD
The Hippo/YAP pathway was dissected in explants of patients transplanted for AH or alcohol-related cirrhosis and in control livers, using RNA-seq, real-time PCR, western blot, immunohistochemistry and transcriptome analysis after laser microdissection. We transfected primary human hepatocytes with constitutively active YAP (YAPS127A) and treated HepaRG cells and primary hepatocytes isolated from AH livers with a YAP inhibitor. We also used mouse models of ethanol exposure (Lieber de Carli) and liver regeneration (carbon tetrachloride) after hepatocyte transduction of YAPS127A.
RESULTS
In AH samples, RNA-seq analysis and immunohistochemistry of total liver and microdissected hepatocytes revealed marked downregulation of the Hippo pathway, demonstrated by lower levels of active MST1 kinase and abnormal activation of YAP in hepatocytes. Overactivation of YAP in hepatocytes in vitro and in vivo led to biliary differentiation and loss of key biological functions such as regeneration capacity. Conversely, a YAP inhibitor restored the mature hepatocyte phenotype in abnormal hepatocytes taken from patients with AH. In ethanol-fed mice, YAP activation using YAPS127A resulted in a loss of hepatocyte differentiation. Hepatocyte proliferation was hampered by YAPS127A after carbon tetrachloride intoxication.
CONCLUSION
Aberrant activation of YAP plays an important role in hepatocyte transdifferentiation in AH, through a loss of hepatocyte identity and impaired regeneration. Thus, targeting YAP is a promising strategy for the treatment of patients with AH.
LAY SUMMARY
Alcoholic hepatitis is characterized by inflammation and a life-threatening alteration of liver regeneration, although the mechanisms behind this have not been identified. Herein, we show that liver samples from patients with alcoholic hepatitis are characterized by profound deregulation of the Hippo/YAP pathway with uncontrolled activation of YAP in hepatocytes. We used human cell and mouse models to show that inhibition of YAP reverts this hepatocyte defect and could be a novel therapeutic strategy for alcoholic hepatitis.
Topics: Animals; Disease Models, Animal; Female; France; Hepatitis, Alcoholic; Hepatocytes; Mice; YAP-Signaling Proteins
PubMed: 34129887
DOI: 10.1016/j.jhep.2021.05.041 -
Revue Medicale de Liege May 2019Alcoholic hepatitis is a syndrome defined primarily by the clinical onset of jaundice in patients with a concomitant heavy consumption of alcoholic beverages. This...
Alcoholic hepatitis is a syndrome defined primarily by the clinical onset of jaundice in patients with a concomitant heavy consumption of alcoholic beverages. This pathology is managed by alcohol withdrawal with a 30-day survival rate of 90 %. For patients with severe alcoholic hepatitis, with a Maddrey score greater than 32 (taking into account bilirubin and prothrombin time), treatment with corticosteroids is discussed provided that a possible infection can be sufficiently excluded or adequately managed. The administration of corticosteroids is continued for 28 days if the Lille score, calculated after 7 days of treatment, is favourable (inferior to 0.45), leading to a survival rate of 80-90 %. However, if the Lille score is unfavourable (superior to 0.45), the prognosis is bad, with a survival of only 25-30 % at 6 months. Special attention needs to be paid to assure a sufficient caloric intake during the treatment period for a successful management. Liver transplantation, previously prohibited for this indication, can be discussed under certain circumstances. However, the success of treatment is contingent upon the alcohol withdrawal. Innovative drugs are currently under investigation to improve the prognosis of this condition.
Topics: Adrenal Cortex Hormones; Bilirubin; Hepatitis, Alcoholic; Humans; Liver Transplantation; Prognosis
PubMed: 31206275
DOI: No ID Found -
American Family Physician Apr 2022Alcoholic 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...
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.
Topics: End Stage Liver Disease; Hepatitis, Alcoholic; Humans; Inflammation; Liver Cirrhosis; Severity of Illness Index
PubMed: 35426628
DOI: No ID Found -
The Medical Clinics of North America May 2023Alcoholic hepatitis (AH) is a unique clinical syndrome on the spectrum of alcohol-associated liver disease (ALD). It constitutes a rising epidemic with increasing... (Review)
Review
Alcoholic hepatitis (AH) is a unique clinical syndrome on the spectrum of alcohol-associated liver disease (ALD). It constitutes a rising epidemic with increasing incidence and major public health implications. In severe AH, 30-day mortality approaches 30%, yet therapeutic options remain limited. Survival benefit from corticosteroids, the mainstay of medical treatment, is short-lived. Among corticosteroid nonresponders, the use of early liver transplantation is heterogeneous across centers and remains limited by significant barriers. Long-term prognosis is largely dictated by abstinence; however, comorbid alcohol use disorder remains undertreated. Efforts to address these challenges are required to curb the AH epidemic.
Topics: Humans; Hepatitis, Alcoholic; Liver Diseases, Alcoholic; Prognosis; Alcohol Drinking; Liver Transplantation; Adrenal Cortex Hormones
PubMed: 37001952
DOI: 10.1016/j.mcna.2022.12.005