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EBioMedicine Jul 2019Alcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH)...
BACKGROUND
Alcohol and obesity synergise to increase the risk of liver-related mortality. We examined the influence of adiposity on clinical outcomes in alcoholic hepatitis (AH) and the underlying inflammatory crosstalk between adipose tissue (AT) and the liver.
METHODS
A cohort of 233 patients with AH from the UK and USA provided data to analyse the effects of obesity in AH. Body mass index was corrected for the severity of ascites, termed cBMI. Inflammatory and metabolic profiling was undertaken by proteome analysis of human serum samples. The effect of alcohol on adipose tissue and CXCL11 expression was studied in 3 T3-derived adipocytes and in mice using the high-fat diet-plus-binge ethanol model.
FINDINGS
Obesity was common amongst patients with AH, seen in 19% of individuals. Obesity (HR 2.22, 95%CI 1.1-4.3, p = .022) and underweight (HR 2.38, 1.00-5.6, p = .049) were independently associated with mortality at 3 months. Proteome analysis demonstrated multiple metabolic and inflammatory factors differentially expressed in obese AH verse lean AH, with CXCL11 being the most elevated factor in obese AH. In vitro analysis of cultured adipocytes and in vivo analysis of mouse models showed that alcohol induced CXCL11 expression in AT, but not in liver.
INTERPRETATION
Obesity is common in AH and associated with a greater than two-fold increase in short-term mortality. Obese AH is associated with a different inflammatory phenotype, with the greatest elevation in CXCL11. These data confirm that adiposity is clinically important in acute alcohol-related liver disease and illustrate the adipose-liver inflammatory axis in AH. FUND: This work was supported in part by an EASL Sheila Sherlock Physician Scientist Fellowship. The funder played no role in gathering or analysing data or writing the manuscript. This paper presents independent research supported by the NIHR Birmingham Biomedical Research Centre at the University Hospitals Birmingham NHS Foundation Trust and the University of Birmingham. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
Topics: Adipocytes; Adipose Tissue; Adiposity; Animals; Chemokine CXCL11; Cohort Studies; Diet, High-Fat; Female; Gene Expression Regulation; Hepatitis, Alcoholic; Humans; Liver; Male; Mice; Morbidity; Obesity
PubMed: 31278069
DOI: 10.1016/j.ebiom.2019.03.046 -
Frontiers in Immunology 2023The hepatoprotective effect of interleukin 22 (IL-22) has been reported in several models of liver injuries, including alcohol-associated liver disease (ALD). However,...
BACKGROUND
The hepatoprotective effect of interleukin 22 (IL-22) has been reported in several models of liver injuries, including alcohol-associated liver disease (ALD). However, the intestinal role of IL-22 in alcoholic hepatitis remains to be elucidated.
METHODS
Intestinal IL-22 levels were measured in mice fed with alcohol for 8 weeks. IL-22 was then administered to alcohol-fed mice to test its protective effects on alleviating alcoholic hepatitis, focusing on intestinal protection. Acute IL-22 treatment was conducted in mice to further explore the link between IL-22 and the induction of antimicrobial peptide (AMP). Intestinal epithelial cell-specific knockout of signal transducer and activator of transcription 3 (STAT3) mice were generated and used for organoid study to explore its role in IL-22-mediated AMP expression and gut barrier integrity.
RESULTS
After alcohol feeding for 8 weeks, the intestinal levels of IL-22 were significantly reduced in mice. IL-22 treatment to alcohol-fed mice mitigated liver injury as indicated by normalized serum transaminase levels, improved liver histology, reduced lipid accumulation, and attenuated inflammation. In the intestine, alcohol-reduced Reg3γ and α-defensins levels were reversed by IL-22 treatment. IL-22 also improved gut barrier integrity and decreased endotoxemia in alcohol-fed mice. While alcohol feeding significantly reduced , IL-22 administration dramatically expanded this commensal bacterium in mice. Regardless of alcohol, acute IL-22 treatment induced a fast and robust induction of intestinal AMPs and STAT3 activation. By using cultured intestinal organoids isolated from WT mice and mice deficient in intestinal epithelial-STAT3, we further demonstrated that STAT3 is required for IL-22-mediated AMP expression. In addition, IL-22 also regulates intestinal epithelium differentiation as indicated by direct regulation of sodium-hydrogen exchanger 3 via STAT3.
CONCLUSION
Our study suggests that IL-22 not only targets the liver but also benefits the intestine in many aspects. The intestinal effects of IL-22 include regulating AMP expression, microbiota, and gut barrier function that is pivotal in ameliorating alcohol induced translocation of gut-derived bacterial pathogens and liver inflammation.
Topics: Mice; Animals; Hepatitis, Alcoholic; Symbiosis; Interleukins; Liver Diseases, Alcoholic; Ethanol; Inflammation; Anti-Infective Agents; Microbiota; Bacteria; Interleukin-22
PubMed: 37908362
DOI: 10.3389/fimmu.2023.1289356 -
ELife Dec 2023The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45)...
The pathogenesis of antibodies in severe alcoholic hepatitis (SAH) remains unknown. We analyzed immunoglobulins (Ig) in explanted livers from SAH patients (n=45) undergoing liver transplantation and tissues from corresponding healthy donors (HD, n=10) and found massive deposition of IgG and IgA isotype antibodies associated with complement fragment C3d and C4d staining in ballooned hepatocytes in SAH livers. Ig extracted from SAH livers, but not patient serum exhibited hepatocyte killing efficacy. Employing human and K12 proteome arrays, we profiled the antibodies extracted from explanted SAH, livers with other diseases, and HD livers. Compared with their counterparts extracted from livers with other diseases and HD, antibodies of IgG and IgA isotypes were highly accumulated in SAH and recognized a unique set of human proteins and antigens. Further, both Ig- and -captured Ig from SAH livers recognized common autoantigens enriched in several cellular components including cytosol and cytoplasm (IgG and IgA), nucleus, mitochondrion, and focal adhesion (IgG). Except IgM from primary biliary cholangitis livers, no common autoantigen was recognized by Ig- and -captured Ig from livers with other diseases. These findings demonstrate the presence of cross-reacting anti-bacterial IgG and IgA autoantibodies in SAH livers.
Topics: Humans; Hepatitis, Alcoholic; Escherichia coli; Immunoglobulin A; Autoantibodies; Immunoglobulin G; Immunoglobulin M
PubMed: 38055614
DOI: 10.7554/eLife.86678 -
Gastroenterology Jun 2016Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history... (Review)
Review
Alcoholic hepatitis (AH) is a syndrome of jaundice and liver failure that occurs in a minority of heavy consumers of alcohol. The diagnosis usually is based on a history of heavy alcohol use, findings from blood tests, and exclusion of other liver diseases by blood and imaging analyses. Liver biopsy specimens, usually collected via the transjugular route, should be analyzed to confirm a diagnosis of AH in patients with an atypical history or presentation. The optimal treatment for patients with severe AH is prednisolone, possibly in combination with N-acetyl cysteine. At present, only short-term increases in survival can be expected-no treatment has been found to increase patient survival beyond 3 months. Abstinence is essential for long-term survival. New treatment options, including liver transplantation, are being tested in trials and results eagerly are awaited.
Topics: Acetylcysteine; Biopsy; Free Radical Scavengers; Glucocorticoids; Hepatitis, Alcoholic; Humans; Liver; Prednisolone; Prognosis
PubMed: 26948886
DOI: 10.1053/j.gastro.2016.02.074 -
Digestive Diseases and Sciences Jun 2020Although alcohol-associated liver disease has long been a major component of the liver disease landscape, it was overshadowed by chronic hepatitis C until recently.... (Review)
Review
Although alcohol-associated liver disease has long been a major component of the liver disease landscape, it was overshadowed by chronic hepatitis C until recently. Nevertheless, with the declining incidence of hepatitis C in the wake of highly effective antiviral therapy, attention has shifted to the increasing burden of alcohol-associated liver disease. The incidence of advanced alcohol-associated liver disease, including acute alcoholic hepatitis and alcohol-associated cirrhosis, is rising in parallel with increasing rates of alcohol use disorders. As a result, alcohol-associated liver disease is now one of the most common indications for liver transplantation. Rates of liver transplantation for acute alcoholic hepatitis are rising as well in spite of the sparse guidance regarding candidate selection, counseling, postoperative care, long-term follow-up, and other best practices. To this day, liver transplant for acute alcoholic hepatitis remains a hotly debated clinical controversy.
Topics: Alcoholism; Female; Graft Survival; Hepatitis, Alcoholic; Humans; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Liver Transplantation; Male; Patient Selection; Treatment Outcome
PubMed: 32107678
DOI: 10.1007/s10620-020-06159-9 -
Dysregulated meta-organismal metabolism of aromatic amino acids in alcohol-associated liver disease.Hepatology Communications Nov 2023Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated... (Comparative Study)
Comparative Study
BACKGROUND
Chronic alcohol consumption impairs gut barrier function and perturbs the gut microbiome. Although shifts in bacterial communities in patients with alcohol-associated liver disease (ALD) have been characterized, less is known about the interactions between host metabolism and circulating microbe-derived metabolites during the progression of ALD.
METHODS
A large panel of gut microbiome-derived metabolites of aromatic amino acids was quantified by stable isotope dilution liquid chromatography with online tandem mass spectrometry in plasma from healthy controls (n = 29), heavy drinkers (n = 10), patients with moderate (n = 16) or severe alcohol-associated hepatitis (n = 40), and alcohol-associated cirrhosis (n = 10).
RESULTS
The tryptophan metabolites, serotonin and indole-3-propionic acid, and tyrosine metabolites, p-cresol sulfate, and p-cresol glucuronide, were decreased in patients with ALD. Patients with severe alcohol-associated hepatitis and alcohol-associated cirrhosis had the largest decrease in concentrations of tryptophan and tyrosine-derived metabolites compared to healthy control. Western blot analysis and interrogation of bulk RNA sequencing data from patients with various liver pathologies revealed perturbations in hepatic expression of phase II metabolism enzymes involved in sulfonation and glucuronidation in patients with severe forms of ALD.
CONCLUSIONS
We identified several metabolites decreased in ALD and disruptions of hepatic phase II metabolism. These results indicate that patients with more advanced stages of ALD, including severe alcohol-associated hepatitis and alcohol-associated cirrhosis, had complex perturbations in metabolite concentrations that likely reflect both changes in the composition of the gut microbiome community and the ability of the host to enzymatically modify the gut-derived metabolites.
Topics: Humans; Amino Acids, Aromatic; Hepatitis; Liver Cirrhosis, Alcoholic; Liver Diseases, Alcoholic; Tryptophan; Tyrosine; Gastrointestinal Microbiome; Hepatitis, Alcoholic; Liver
PubMed: 37820283
DOI: 10.1097/HC9.0000000000000284 -
World Journal of Gastroenterology Oct 2014Alcoholic liver disease encompasses a broad spectrum of diseases ranging from steatosis steatohepatitis, fibrosis, and cirrhosis to hepatocellular carcinoma. Forty-four... (Review)
Review
Alcoholic liver disease encompasses a broad spectrum of diseases ranging from steatosis steatohepatitis, fibrosis, and cirrhosis to hepatocellular carcinoma. Forty-four per cent of all deaths from cirrhosis are attributed to alcohol. Alcoholic liver disease is the second most common diagnosis among patients undergoing liver transplantation (LT). The vast majority of transplant programmes (85%) require 6 mo of abstinence prior to transplantation; commonly referred to as the "6-mo rule". Both in the case of progressive end-stage liver disease (ESLD) and in the case of severe acute alcoholic hepatitis (AAH), not responding to medical therapy, there is a lack of evidence to support a 6-mo sobriety period. It is necessary to identify other risk factors that could be associated with the resumption of alcohol drinking. The "Group of Italian Regions" suggests that: in a case of ESLD with model for end-stage liver disease < 19 a 6-mo abstinence period is required; in a case of ESLD, a 3-mo sober period before LT may be more ideal than a 6-mo period, in selected patients; and in a case of severe AAH, not responding to medical therapies (up to 70% of patients die within 6 mo), LT is mandatory, even without achieving abstinence. The multidisciplinary transplant team must include an addiction specialist/hepato-alcohologist. Patients have to participate in self-help groups.
Topics: Alcohol Abstinence; Comorbidity; Hepatitis, Alcoholic; Humans; Italy; Liver Cirrhosis, Alcoholic; Liver Transplantation; Patient Care Team; Patient Selection; Risk Assessment; Risk Factors; Self-Help Groups; Severity of Illness Index; Time Factors; Treatment Outcome; Waiting Lists
PubMed: 25356027
DOI: 10.3748/wjg.v20.i40.14642 -
World Journal of Gastroenterology Oct 2010Alcoholic hepatitis (AH) remains a common and life threatening cause of liver failure, especially when it is severe. Although the adjective "acute" is frequently used to... (Review)
Review
Alcoholic hepatitis (AH) remains a common and life threatening cause of liver failure, especially when it is severe. Although the adjective "acute" is frequently used to describe this form of liver injury, it is usually subacute and has been developing for weeks to months before it becomes clinically apparent. Patients with this form of alcoholic liver disease usually have a history of drinking heavily for many years. While certain aspects of therapy, mainly nutritional support and abstinence are well established, significant debate has surrounded the pharmacologic treatment of AH, and many institutions practice widely varying treatment protocols. In recent years a significant amount of literature has helped focus on the details of treatment, and more data have accumulated regarding risks and benefits of pharmacologic treatment. In particular, the efficacy of pentoxifylline has become increasingly apparent, and when compared with the risks associated with prednisolone, has brought this drug to the forefront of therapy for severe AH. This review will focus on the clinical and laboratory diagnosis and pharmacologic therapies that should be applied during hospitalization and continued into outpatient management. We conclude that the routine use of glucocorticoids for severe AH poses significant risk with equivocal benefit, and that pentoxifylline is a better, safer and cheaper alternative. While the full details of nutritional support lie beyond the scope of this article, nutrition is a cornerstone of therapy and must be addressed in every patient diagnosed with AH. Finally, while traditional psychosocial techniques play a major role in post-hospitalization care of alcoholics, we hope to make the medical clinician realize his or her role in reducing recidivism rates with early and frequent outpatient visits and with the use of baclofen to reduce alcohol craving.
Topics: Alcohol Deterrents; Alcohol Drinking; Anti-Inflammatory Agents; Baclofen; Combined Modality Therapy; Continuity of Patient Care; Glucocorticoids; Hepatitis, Alcoholic; Humans; Nutritional Support; Pentoxifylline; Predictive Value of Tests; Prednisolone; Severity of Illness Index; Treatment Outcome
PubMed: 20954276
DOI: 10.3748/wjg.v16.i39.4905 -
World Journal of Gastroenterology Apr 2016The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most... (Review)
Review
The burden of alcoholic liver disease has rapidly grown in the past two decades and is expected to increase further in the coming years. Alcoholic hepatitis, the most florid presentation of alcoholic liver disease, continues to have high morbidity and mortality, with significant financial and healthcare burden with limited treatment options. Steroids remain the current standard of care in severe alcoholic hepatitis in carefully selected patients. No specific treatments are available for those patients who are steroid ineligible, intolerant or unresponsive. Liver transplant has shown good short-term outcome; however, feasibility, ethical and economic concerns remain. Modification of gut microbiota composition and their products, such as lipopolysaccharide, nutritional interventions, immune modulation, increasing steroid sensitivity, genetic polymorphism and epigenetic modification of alcohol induced liver damage, augmenting hepatic regeneration using GCSF are potential therapeutic avenues in steroid non-responsive/ineligible patients. With better understanding of the pathophysiology, using "Omics" platforms, newer options for patients with alcoholic hepatitis are expected soon.
Topics: Anti-Bacterial Agents; Anti-Inflammatory Agents; Drug Resistance; Gastrointestinal Microbiome; Gastrointestinal Tract; Genetic Therapy; Hepatitis, Alcoholic; Humans; Liver Transplantation; Nutritional Support; Pentoxifylline; Prebiotics; Probiotics; Steroids; Treatment Outcome
PubMed: 27099434
DOI: 10.3748/wjg.v22.i15.3892 -
Clinical and Molecular Hepatology Oct 2020Severe alcoholic hepatitis (AH) is an acute and often devastating form of alcohol-associated liver disease. Clinically, AH is characterized by elevated bilirubin, model... (Review)
Review
Severe alcoholic hepatitis (AH) is an acute and often devastating form of alcohol-associated liver disease. Clinically, AH is characterized by elevated bilirubin, model for end stage liver disease scores >20, and nonspecific symptoms that are caused by underlying inflammation, hepatocyte injury, and impaired intestinal barrier function. Compromised immune defense in AH contributes to infections, sepsis and organ failure. To date, corticosteroids are the only recommended treatment for severe AH, however it does not provide survival benefits beyond 1 month. Recent preclinical and early clinical studies in AH aided understanding of the disease and presented opportunities for new therapeutic options targeting inflammation, oxidative stress, liver regeneration and modification of intestinal microbiota. In this comprehensive review, we discuss promising preclinical results and ongoing clinical trials evaluating novel therapeutic agents for the treatment of severe AH.
Topics: End Stage Liver Disease; Hepatitis, Alcoholic; Humans; Inflammation; Severity of Illness Index
PubMed: 32981291
DOI: 10.3350/cmh.2020.0145