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Journal of Xenobiotics Sep 2022Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis... (Review)
Review
Alcoholic hepatitis is a major health and economic burden worldwide. Glucocorticoids (GCs) are the only first-line drugs recommended to treat severe alcoholic hepatitis (sAH), with limited short-term efficacy and significant side effects. In this review, I summarize the major benefits and side effects of GC therapy in sAH and the potential underlying mechanisms. The review of the literature and data mining clearly indicate that the hepatic signaling of glucocorticoid receptor (GR) is markedly impaired in sAH patients. The impaired GR signaling causes hepatic down-regulation of genes essential for gluconeogenesis, lipid catabolism, cytoprotection, and anti-inflammation in sAH patients. The efficacy of GCs in sAH may be compromised by GC resistance and/or GC's extrahepatic side effects, particularly the side effects of intestinal epithelial GR on gut permeability and inflammation in AH. Prednisolone, a major GC used for sAH, activates both the GR and mineralocorticoid receptor (MR). When GC non-responsiveness occurs in sAH patients, the activation of MR by prednisolone might increase the risk of alcohol abuse, liver fibrosis, and acute kidney injury. To improve the GC therapy of sAH, the effort should be focused on developing the biomarker(s) for GC responsiveness, liver-targeting GR agonists, and strategies to overcome GC non-responsiveness and prevent alcohol relapse in sAH patients.
PubMed: 36278756
DOI: 10.3390/jox12040019 -
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 -
International Journal of Molecular... Sep 2023Alcoholic hepatitis (AH) is a rapidly progressing and severe stage of alcoholic liver disease, presenting a grim prognosis. Extensive research has elucidated several... (Review)
Review
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.
Topics: Humans; Hepatitis, Alcoholic; Gastrointestinal Microbiome; Liver Diseases, Alcoholic; Forecasting; Dysbiosis
PubMed: 37834256
DOI: 10.3390/ijms241914809 -
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 -
Journal of Hepatology Jul 2021Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and...
BACKGROUND & AIMS
Interleukin (IL)-20 and IL-22 belong to the IL-10 family. IL-10 is a well-documented anti-inflammatory cytokine while IL-22 is well known for epithelial protection and its antibacterial function, showing great therapeutic potential for organ damage; however, the function of IL-20 remains largely unknown.
METHODS
Il20 knockout (Il20) mice and wild-type littermates were generated and injected with Concanavalin A (ConA) and Klebsiella pneumoniae (K.P.) to induce acute hepatitis and bacterial infection, respectively.
RESULTS
Il20 mice were resistant to acute hepatitis and exhibited selectively elevated levels of the hepatoprotective cytokine IL-6. Such selective inhibition of IL-6 by IL-20 was due to IL-20 targeting hepatocytes that produce high levels of IL-6 but a limited number of other cytokines. Mechanistically, IL-20 upregulated NAD(P)H: quinone oxidoreductase 1 (NQO1) expression and subsequently promoted the protein degradation of transcription factor IκBζ, resulting in selective downregulation of the IκBζ-dependent gene Il6 as well several other IκBζ-dependent genes including lipocalin-2 (Lcn2). Given the important role of IL-6 and LCN2 in limiting bacterial infection, we examined the effect of IL-20 on bacterial infection and found Il20 mice were resistant to K.P. infection and exhibited elevated levels of hepatic IκBζ-dependent antibacterial genes. Moreover, IL-20 upregulated hepatic NQO1 by binding to IL-22R1/IL-20R2 and activating ERK/p38MAPK/NRF2 signaling pathways. Finally, the levels of hepatic IL1B, IL20, and IκBζ target genes were elevated, and correlated with each other, in patients with severe alcoholic hepatitis.
CONCLUSIONS
IL-20 selectively inhibits hepatic IL-6 production rather than exerting IL-10-like broad anti-inflammatory properties. Unlike IL-22, IL-20 aggravates acute hepatitis and bacterial infection. Thus, anti-IL-20 therapy could be a promising option to control acute hepatitis and bacterial infection.
LAY SUMMARY
Several interleukin (IL)-20 family cytokines have been shown to play important roles in controllimg inflammatory responses, infection and tissue damage, but the role of IL-20 remains unclear. Herein, we elucidated the role of IL-20 in liver disease and bacterial infection. We show that IL-20 can aggravate hepatitis and bacterial infection; thus, targeting IL-20 holds promise for the treatment of patients with liver disease.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bacterial Infections; Drug Discovery; Gene Expression Regulation; Hepatitis; Hepatitis, Alcoholic; Humans; Interleukin-1beta; Interleukins; Liver; Mice; Mice, Knockout; NAD(P)H Dehydrogenase (Quinone); Proteolysis; Up-Regulation
PubMed: 33610678
DOI: 10.1016/j.jhep.2021.02.004 -
Journal of Clinical and Experimental... 2023Alcohol-associated hepatitis has a poor prognosis in terms of short-term mortality and often presents with symptoms, such as jaundice, acute renal failure, and ascites.... (Review)
Review
Alcohol-associated hepatitis has a poor prognosis in terms of short-term mortality and often presents with symptoms, such as jaundice, acute renal failure, and ascites. There are many prognostic models that have been developed to predict short-term and long-term mortality in these patients. Current prognostic models can be divided into static scores, which are measured at admission, and dynamic models, which measure baseline and after a certain amount of time. The efficacy of these models in predicting short-term mortality is disputed. Numerous studies across the world have compared prognostic models, such as the Maddrey's discriminant function, the model for end-stage liver disease score, model for end-stage liver disease score-Na, Glasgow alcohol-associated hepatitis score, and the age-bilirubin-international normalized ratio-creatinine (ABIC) score, to each other to determine which score is more useful for a particular context. There are also prognostic markers such as liver biopsy, breath biomarkers, and acute kidney injury that are able to predict mortality. The accuracy of these scores is a key to determining when treatment with corticosteroids is futile since there is an increased risk of infection in those treated with it. Furthermore, although these scores are helpful in predicting short-term mortality, the only factor that is able to predict long-term mortality in patients with alcohol-related liver disease is abstinence. Numerous studies have proven that even though corticosteroids provide a treatment for alcohol-associated hepatitis, it is a temporary one, at best. The purpose of this paper is to compare the historical models to current ones in their ability to predict mortality in patients with alcohol-related liver disease by analyzing multiple studies that have examined these prognostic markers. This paper also isolates the knowledge gaps in the ability to delineate which patients would benefit from corticosteroids and patients who would not and provides potential models for the future that could narrow this gap.
PubMed: 37250869
DOI: 10.1016/j.jceh.2022.10.010 -
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 -
Journal of Clinical and Experimental... 2023Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol... (Review)
Review
Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10-35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD.
PubMed: 36647400
DOI: 10.1016/j.jceh.2022.09.001 -
Liver International : Official Journal... Mar 2020
Topics: Ethanol; Hepatitis, Alcoholic; Humans; Prognosis; Recurrence
PubMed: 32124541
DOI: 10.1111/liv.14343