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Fu S, Pan JH, Kadri H, Contag C, Ferguson J, Sedki M, Kwong A, Goel A, Melcher ML. Perioperative Outcomes of Limited Sobriety Versus Standard Sobriety Liver Transplantation for Alcohol-associated Liver Disease. Transplant Proc 2025; 57:585-592. [PMID: 40113492 DOI: 10.1016/j.transproceed.2025.02.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2024] [Revised: 01/23/2025] [Accepted: 02/10/2025] [Indexed: 03/22/2025]
Abstract
Alcohol-associated liver disease is now the leading indication for liver transplantation in the United States in the context of liver transplantation for patients with less than 6 months of abstinence from alcohol. To determine whether patients with less than 6 months of sobriety have worse perioperative outcomes than those with standard sobriety requirements, we performed a retrospective cohort study, comparing limited and standard sobriety patients undergoing orthotopic liver transplantation from May 2018 to October 2022 at a single academic tertiary transplant center. The limited sobriety cohort comprised adult patients with end-stage liver disease secondary to alcohol use disorder who presented with their first episode of hepatic decompensation, with less than 6 months of sobriety. This group was compared with a standard sobriety cohort, consisting of patients with alcohol-associated liver disease with more than 6 months of sobriety. A total of 169 patients were selected for analysis, with 58 in the limited sobriety group and 111 in the standard sobriety group. The limited- sobriety group was younger (median 42 years vs 54 years; P < .01) and had more severe liver disease than the standard sobriety group (median Model for End-stage Liver Disease scores of 39 vs 34; P < .01) at the time of transplantation. There were no statistically significant differences in the primary outcomes between the 2 groups. Despite having more severe liver disease, the limited sobriety management pathway was not associated with worse perioperative outcomes than the standard sobriety pathway. Our findings indicate liver transplantation in patients with limited sobriety do not require increased perioperative resources.
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Affiliation(s)
- Sue Fu
- Department of Surgery, Stanford University School of Medicine, Stanford, California.
| | - Jenny H Pan
- Department of Surgery, Stanford University School of Medicine, Stanford, California
| | - Haaris Kadri
- Department of Surgery, Stanford University School of Medicine, Stanford, California
| | - Caitlin Contag
- Department of Infectious Diseases, Stanford University School of Medicine, Stanford, California
| | - Jessica Ferguson
- Department of Infectious Diseases, Stanford University School of Medicine, Stanford, California
| | - Mai Sedki
- Department of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, California
| | - Allison Kwong
- Department of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, California; Stanford Transplant Outcomes Research Center (STORC), Stanford, California
| | - Aparna Goel
- Department of Gastroenterology & Hepatology, Stanford University School of Medicine, Stanford, California
| | - Marc L Melcher
- Department of Surgery, Stanford University School of Medicine, Stanford, California; Stanford Transplant Outcomes Research Center (STORC), Stanford, California
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Rady ED, Anouti A, Mitchell MC, Cotter TG. Current Clinical Trials for Alcohol-Associated Hepatitis. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00116-6. [PMID: 40254132 DOI: 10.1016/j.ajpath.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2025] [Revised: 03/22/2025] [Accepted: 03/28/2025] [Indexed: 04/22/2025]
Abstract
Alcohol-associated hepatitis (AH) is a severe form of alcohol-associated liver disease characterized by acute-onset jaundice and liver failure. AH carries a high mortality risk, particularly in severe cases. Although glucocorticoids have been the primary pharmacologic intervention for decades, their use is limited by a lack of long-term efficacy and significant side effects and relative contraindications. For patients who do not respond to glucocorticoids, early liver transplantation is a life-saving option; only a few patients qualify for this intervention, however. In recent years, advances in translational medicine have uncovered key mechanisms in AH pathophysiology, including microbiome interactions, proinflammatory signaling, and disruptions in hepatocyte function. These insights have led to the exploration of innovative pharmacologic treatments, targeting pathways such as the gut-liver axis, oxidative stress, inflammation, and liver regeneration. Despite promising results from ongoing clinical trials, several challenges persist, including low patient recruitment and retention rates, heterogeneity in trial design, and the lack of standardized endpoints. This review assesses the current pharmacologic landscape of AH, emphasizing emerging therapies and the ongoing challenges in AH clinical trials.
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Affiliation(s)
- Elias D Rady
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Ahmad Anouti
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas
| | - Thomas G Cotter
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, Texas.
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Yamazaki T, Schnabl B. Acute alcohol-associated hepatitis: Latest findings in non-invasive biomarkers and treatment. Liver Int 2025; 45:e15608. [PMID: 37183549 PMCID: PMC10646153 DOI: 10.1111/liv.15608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 04/15/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023]
Abstract
Acute alcohol-associated hepatitis (AH) is a syndrome that occurs in heavy and long-term drinkers and results in severe jaundice and liver failure. The mortality rate in severe cases is 20%-50% at 28 days, and in cases that do not improve despite appropriately timed corticosteroid therapy, the mortality rate reaches 70% at 6 months. The only curative treatment is early liver transplantation, but less than 2% of patients with severe AH are eligible. In order to improve the prognosis, diagnostic tools are needed to detect appropriate cases at risk of severe conditions, and new therapies need to be developed that can replace corticosteroids. Recent research has revealed that the pathogenesis of AH involves a complex of factors, including changes in the gut microbiota, inflammatory and cytokine signalling, oxidative stress and mitochondrial dysfunction, and abnormalities in the hepatic regenerative capacity. Non-invasive diagnostic tools focusing on these specific pathologies have been reported in recent years. In addition, several novel agents targeting specific pathways are currently being developed and tested in clinical trials. This review will provide an overview of alcohol-associated hepatitis and focus on the latest diagnostic tools, particularly non-invasive biomarkers, and novel therapies.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Nagano, Matsumoto, Japan
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, California, San Diego, USA
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Nguyen CM, Su J, Li Y, Healey R, Jiang S, Li J, Chalasani N, Gawrieh S, Liangpunsakul S, Tu W. Short-term costs of alcohol-associated hepatitis care in different clinical settings. Hepatol Commun 2025; 9:e0634. [PMID: 39878651 PMCID: PMC11781763 DOI: 10.1097/hc9.0000000000000634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 12/09/2024] [Indexed: 01/31/2025] Open
Abstract
BACKGROUND Alcohol-associated hepatitis (AH) leads to high rates of mortality and health care costs. Understanding the immediate costs after an AH diagnosis and identifying key cost factors is crucial for health care policies and clinical decisions. OBJECTIVES This study quantifies medical costs within 30 days of an AH diagnosis across outpatient (OP), emergency department (ED), and inpatient (IP) settings. It also explores concurrent diagnoses and their effects on care costs. METHODS We conducted a retrospective cohort study using deidentified data from Optum's Clinformatics Data Mart. The cohort included individuals aged 21 years and older diagnosed with AH from January 1, 2016, to September 30, 2023. Patients were categorized by care setting (OP, ED, or IP). Costs were calculated for the 30 days before and after AH diagnosis and adjusted to 2023-dollar values. Comorbidities were identified using Elixhauser comorbidity software, and multivariable linear regression models were used to analyze medical costs. RESULTS The cohort included 34,974 individuals diagnosed with AH: 8048 in OP (23%), 2736 in ED (7.8%), and 24,190 in IP (69.2%). Average spending in the 30 days prior to AH diagnosis was $7334 for OP, $5740 for ED, and $14,458 for IP. Following AH diagnosis, average costs rose to $8345 for OP, $20,990 for ED, and $88,655 for IP, reflecting increases of 14%, 266%, and 413%, respectively. Significant cost drivers in IP included comorbidities associated with moderate-to-severe liver disease, metabolic syndrome, liver transplant, and mortality during the 30-day follow-up period. CONCLUSIONS Immediate costs following an AH diagnosis are substantial, particularly for IP care. Costs increase significantly with high-cost comorbidity clusters and among patients who die, underscoring the need for effective management of comorbidities in AH care.
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Affiliation(s)
- Chi Mai Nguyen
- Department of Biostatistics & Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jing Su
- Department of Biostatistics & Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yang Li
- Department of Biostatistics & Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ryan Healey
- Department of Biostatistics & Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Shihui Jiang
- Department of Biostatistics & Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jiangqiong Li
- Department of Biostatistics & Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Naga Chalasani
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Samer Gawrieh
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Wanzhu Tu
- Department of Biostatistics & Health Data Science, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Regenstrief Institute Inc., Indianapolis, Indiana, USA
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Islam AH, Díaz LA, Idalsoaga F, Guizzetti L, Mortuza R, Dunn W, Singal AK, Simonetto D, Ramirez-Cadiz C, Zhang W, Qian S, Cabezas J, Sarin SK, Maiwall R, Jalal PK, Higuera-De La Tijera F, Skladany L, Bystrianska N, Rincon D, Chacko KR, Ventura Cots M, Garcia-Tsao G, Abraldes JG, Kamath PS, Arrese M, Shah V, Bataller R, Arab JP. Comparative effectiveness of different corticosteroid regimens in severe alcohol-associated hepatitis. Hepatol Commun 2024; 8:e0573. [PMID: 39445912 PMCID: PMC11512629 DOI: 10.1097/hc9.0000000000000573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2024] [Accepted: 08/22/2024] [Indexed: 10/25/2024] Open
Affiliation(s)
- Alvi Husni Islam
- Department of Medicine, Division of Gastroenterology, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
| | - Luis Antonio Díaz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- MASLD Research Center, Department of Medicine, Division of Gastroenterology and Hepatology, University of California San Diego, San Diego, California, USA
| | - Francisco Idalsoaga
- Department of Medicine, Division of Gastroenterology, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Rokhsana Mortuza
- Department of Medicine, Division of Gastroenterology, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
| | - Winston Dunn
- Department of Medicine, Division of Gastroenterology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Ashwani K. Singal
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, Kentucky, USA
| | - Douglas Simonetto
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Carolina Ramirez-Cadiz
- Department of Anesthesia, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
| | - Wei Zhang
- Gastroenterology Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Steve Qian
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Florida, Gainesville, Florida, USA
| | - Joaquín Cabezas
- Gastroenterology and Hepatology Department, University Hospital Marqués de Valdecilla, Research Institute Valdecilla (IDIVAL), Santander, Spain
| | - Shiv K. Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rakhi Maiwall
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Prasun K. Jalal
- Department of Gastroenterology and Hepatology, Baylor College of Medicine, Houston, Texas, USA
| | - Fatima Higuera-De La Tijera
- Servicio de Gastroenterología, Hospital General de Mexico, Universidad Nacional Autónoma de Mexico, Ciudad de Mexico, Mexico
| | - Lubomir Skladany
- Department of Internal Medicine II, Division of Hepatology, Gastroenterology and Liver Transplantation, Slovak Medical University, F.D. Roosevelt University Hospital, Banska Bystrica, Slovak Republic
| | - Natalia Bystrianska
- Department of Internal Medicine II, Division of Hepatology, Gastroenterology and Liver Transplantation, Slovak Medical University, F.D. Roosevelt University Hospital, Banska Bystrica, Slovak Republic
| | - Diego Rincon
- Liver Unit, Department of Digestive Diseases, Hospital General Universitario Gregorio Marañón, CIBEREHD Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Madrid, Spain
| | - Kristina R. Chacko
- Division of Gastroenterology and Hepatology, Montefiore Medical Center, Bronx, New York, USA
| | - Meritxell Ventura Cots
- Liver Unit, Hospital Vall d’Hebron, Universitat Autonoma Barcelona, CIBEREHD, Barcelona, Spain
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine/VA-CT Healthcare System, New Haven/West Haven, Connecticut, USA
| | - Juan G. Abraldes
- Department of Medicine, Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Alberta, Canada
| | - Patrick S. Kamath
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Marco Arrese
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Vijay Shah
- Department of Medicine, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Ramon Bataller
- Liver Unit, Hospital Clinic, Barcelona, Spain
- Department of Medicine, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA
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6
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Mandrekar P, Mandal A. Pathogenesis of Alcohol-Associated Liver Disease. Clin Liver Dis 2024; 28:647-661. [PMID: 39362713 DOI: 10.1016/j.cld.2024.06.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
The pathogenesis of alcohol-associated liver disease (ALD) is complex and multifactorial. Several intracellular, intrahepatic, and extrahepatic factors influence development of early fatty liver injury leading to inflammation and fibrosis. Alcohol metabolism, cellular stress, and gut-derived factors contribute to hepatocyte and immune cell injury leading to cytokine and chemokine production. The pathogenesis of alcohol-associated hepatitis (AH), an advanced form of acute-on-chronic liver failure due to excessive chronic intake in patients with underlying liver disease, is not well understood. While pathogenic mechanisms in early ALD are studied, the pathogenesis of AH requires further investigation to help design effective drugs for patients.
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Affiliation(s)
- Pranoti Mandrekar
- Department of Medicine, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, MA 01605, USA.
| | - Abhishek Mandal
- Department of Medicine, University of Massachusetts Chan Medical School, 364 Plantation Street, Worcester, MA 01605, USA
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7
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Sengupta S, Anand A, Lopez R, Weleff J, Wang PR, Bellar A, Attaway A, Welch N, Dasarathy S. Emergency services utilization by patients with alcohol-associated hepatitis: An analysis of national trends. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:98-109. [PMID: 38193831 PMCID: PMC10783841 DOI: 10.1111/acer.15223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 10/10/2023] [Accepted: 11/03/2023] [Indexed: 01/10/2024]
Abstract
BACKGROUND Hospitalization and mortality in patients with alcohol-associated hepatitis (AH), a severe form of liver disease, continue to increase over time. Given the severity of the illness, most hospitalized patients with AH are admitted from the emergency department (ED). However, there are no data on ED utilization by patients with AH. Thus, the Nationwide Emergency Department Sample (NEDS) dataset was analyzed to determine the ED utilization for AH. METHODS Temporal trends (2016-2019) and outcomes of ED visits for AH were determined. Primary or secondary AH diagnoses were based on coding priority. Numbers of patients evaluated in the ED, severity of disease, complications of liver disease, and discharge disposition were analyzed. Crude and adjusted rates were examined, and temporal trends evaluated using logistic regression with orthogonal polynomial contrasts for each year. RESULTS There were 466,014,370 ED visits during 2016-2019, of which 448,984 (0.096%) were for AH, 85.0% of which required hospitalization. The rate of visits for AH (primary and secondary) between 2016 and 2019 increased from 85 to 106.8/100,000 ED visits. The rate of secondary AH increased more than the rate of primary AH (from 68.6 to 86.5 vs. from 16.4 to 20.3/100,000 ED visits). Patients aged 45-64 years had the highest rate of ED visits for AH, which decreased during the study period, while the rate of ED visits for AH increased in those aged 25-44 years (from 38.5% to 42.9%). The severity of disease (ascites, hepatic encephalopathy, and acute kidney injury) also increased over time. Medicaid and private insurance were the most common payors for patients seeking care in the ED for AH. CONCLUSIONS Temporal trends show an overall increase in ED utilization rates for AH, more patients requiring hospitalization, and an increase in the proportion of younger patients presenting to the ED with AH.
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Affiliation(s)
- Shreya Sengupta
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
| | - Akhil Anand
- Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, USA
- Department of Psychiatry, University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Rocio Lopez
- Center for Populations Health Research, Cleveland Clinic, Cleveland, OH, USA
| | - Jeremy Weleff
- Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, OH, USA
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, New Haven, CT, 06511, USA
| | - Philip R Wang
- Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Annette Bellar
- Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Amy Attaway
- Pulmonary Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Nicole Welch
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
- Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
| | - Srinivasan Dasarathy
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA
- Inflammation and Immunity, Cleveland Clinic, Cleveland, OH, USA
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8
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Zhou S, Zhong H, Wang Y, Wang X, Pan H, Liu X, Hu L. JNK/MAPK pathway regulation by BEX2 gene silencing in alcoholic hepatitis mice: Effects on oxidative stress. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2023; 47:1869-1882. [PMID: 37864534 DOI: 10.1111/acer.15178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/11/2023] [Accepted: 08/18/2023] [Indexed: 10/23/2023]
Abstract
BACKGROUND Alcoholic hepatitis (AH) is a severe alcoholic-related liver disease that is a leading cause of morbidity and mortality, for which effective treatments are lacking. Brain-expressed X-linked gene 2 (BEX2) has been implicated in various diseases, but its association with AH has received limited attention. Thus, this study investigated BEX2's impact on the progression of AH by affecting the c-Jun NH2-terminal kinase/mitogen-activated protein kinase (JNK/MAPK) pathway. METHODS Microarray dataset GSE28619 from the Gene Expression Omnibus database was used to identify differentially expressed genes in AH. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), Western blot analysis, and flow cytometry were used to measure various factors in the liver tissue of AH mice. RESULTS BEX2 expression was significantly upregulated in the model. BEX2 gene silencing increased the levels of glutathione peroxidase and superoxide dismutase while decreasing malondialdehyde content; phosphorylation of JNK, c-JUN, and p38MAPK; apoptosis rate; and the extent of JNK/MAPK pathway activation. CONCLUSIONS These findings provide valuable insights into the mechanisms underlying AH development and highlight the potential role of BEX2 gene expression as a promising therapeutic target for AH.
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Affiliation(s)
- Shuai Zhou
- Department of General Surgery, Anhui No. 2 Provincial People's Hospital, Anhui Medical University, Hefei, China
| | - Hai Zhong
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Yong Wang
- Department of General Surgery, Anhui No. 2 Provincial People's Hospital, Anhui Medical University, Hefei, China
| | - Xiaoguang Wang
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Hongtao Pan
- Department of General Surgery, Anhui No. 2 Provincial People's Hospital, Anhui Medical University, Hefei, China
| | - Xiaolin Liu
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Lingyu Hu
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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9
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Khan RS, Lalor PF, Thursz M, Newsome PN. The role of neutrophils in alcohol-related hepatitis. J Hepatol 2023; 79:1037-1048. [PMID: 37290590 DOI: 10.1016/j.jhep.2023.05.017] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 05/24/2023] [Accepted: 05/25/2023] [Indexed: 06/10/2023]
Abstract
Alcohol-related liver disease is a major cause of liver disease-associated mortality, with inpatient care being a major contributor to its clinical and economic burden. Alcohol-related hepatitis (AH) is an acute inflammatory form of alcohol-related liver disease. Severe AH is associated with high short-term mortality, with infection being a common cause of death. The presence of AH is associated with increased numbers of circulating and hepatic neutrophils. We review the literature on the role of neutrophils in AH. In particular, we explain how neutrophils are recruited to the inflamed liver and how their antimicrobial functions (chemotaxis, phagocytosis, oxidative burst, NETosis) may be altered in AH. We highlight evidence for the existence of 'high-density' and 'low-density' neutrophil subsets. We also describe the potentially beneficial roles of neutrophils in the resolution of injury in AH through their effects on macrophage polarisation and hepatic regeneration. Finally, we discuss how manipulation of neutrophil recruitment/function may be used as a therapeutic strategy in AH. For example, correction of gut dysbiosis in AH could help to prevent excess neutrophil activation, or treatments could aim to enhance miR-223 function in AH. The development of markers that can reliably distinguish neutrophil subsets and of animal models that accurately reproduce human disease will be crucial for facilitating translational research in this important field.
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Affiliation(s)
- Reenam S Khan
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Patricia F Lalor
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK
| | - Mark Thursz
- Hepatology Unit, Imperial College School of Medicine, St. Mary's Hospital, London, W21NY, England, UK
| | - Philip N Newsome
- Centre for Liver and Gastrointestinal Research, Institute of Immunology and Inflammation, and National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK.
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10
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Brown ZJ, Ruff SM, Pawlik TM. The effect of liver disease on hepatic microenvironment and implications for immune therapy. Front Pharmacol 2023; 14:1225821. [PMID: 37608898 PMCID: PMC10441240 DOI: 10.3389/fphar.2023.1225821] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 07/31/2023] [Indexed: 08/24/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the fourth leading cause of cancer-related death worldwide. HCC often occurs in the setting of chronic liver disease or cirrhosis. Recent evidence has highlighted the importance of the immune microenvironment in the development and progression of HCC, as well as its role in the potential response to therapy. Liver disease such as viral hepatitis, alcohol induced liver disease, and non-alcoholic fatty liver disease is a major risk factor for the development of HCC and has been demonstrated to alter the immune microenvironment. Alterations in the immune microenvironment may markedly influence the response to different therapeutic strategies. As such, research has focused on understanding the complex relationship among tumor cells, immune cells, and the surrounding liver parenchyma to treat HCC more effectively. We herein review the immune microenvironment, as well as the relative effect of liver disease on the immune microenvironment. In addition, we review how changes in the immune microenvironment can lead to therapeutic resistance, as well as highlight future strategies aimed at developing the next-generation of therapies for HCC.
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Affiliation(s)
- Zachary J. Brown
- Department of Surgery, New York University Long Island School of Medicine, Mineola, NY, United States
| | - Samantha M. Ruff
- James Comprehensive Cancer Center, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Timothy M. Pawlik
- James Comprehensive Cancer Center, Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, United States
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11
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Vannier AGL, Przybyszewski EM, Shay J, Patel SJ, Schaefer E, Goodman RP, Luther J. Psychotherapy for Alcohol Use Disorder Is Associated With Reduced Risk of Incident Alcohol-Associated Liver Disease. Clin Gastroenterol Hepatol 2023; 21:1571-1580.e7. [PMID: 35964893 PMCID: PMC9918606 DOI: 10.1016/j.cgh.2022.08.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 08/01/2022] [Accepted: 08/02/2022] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Alcohol-associated liver disease (ALD) is a devastating complication of alcohol use disorder (AUD). Once it develops, ALD is exceedingly difficult to treat; it therefore is critical to identify ways to prevent ALD. By treating the causes of increased alcohol consumption, psychotherapy may offer prophylactic benefit against the development of ALD for patients with AUD. METHODS In this retrospective cohort study, we used International Classification of Diseases, 9th and 10th revision, codes to identify 9635 patients with AUD in the Mass General Brigham Biobank. The mean follow-up period from AUD diagnosis was 9.2 years. We used Cox regression models to generate hazard ratios (HR) for the development of ALD given the receipt or nonreceipt of psychotherapy, adjusting for a range of other contributors including the receipt of medication-assisted treatment. RESULTS In our cohort, 60.4% of patients were men, 83.5% of patients were white, the median age was 57.0 years, and 3544 patients (36.8%) received psychotherapy. ALD developed in 1135 patients (11.8%). In multivariable analysis, psychotherapy was associated with a reduced rate of ALD (HR, 0.59; 95% CI, 0.50-0.71; P < .001). This association held for both individual psychotherapy (HR, 0.70; 95% CI, 0.56-0.86; P < .001) and group psychotherapy (HR, 0.76; 95% CI, 0.61-0.94; P = .01). Among patients with cirrhosis, psychotherapy was associated with a lower rate of hepatic decompensation (HR, 0.68; 95% CI, 0.48-0.95; P = .03). CONCLUSIONS The receipt of psychotherapy in the setting of AUD is associated with reduced incidence and progression of ALD. Given the safety and potential benefit of psychotherapy, clinicians should consider using it to prevent the development of ALD.
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Affiliation(s)
- Augustin G L Vannier
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | | | - Jessica Shay
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Suraj J Patel
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Esperance Schaefer
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Russell P Goodman
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts
| | - Jay Luther
- Massachusetts General Hospital Alcohol Liver Center, Massachusetts General Hospital, Boston, Massachusetts; Gastrointestinal Unit, Massachusetts General Hospital, Boston, Massachusetts.
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12
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Correlation Between Computed Tomography Findings and the Laboratory Test-Derived Severity Score in Patients With Severe Acute Alcoholic Hepatitis. J Comput Assist Tomogr 2023:00004728-990000000-00153. [PMID: 36877790 DOI: 10.1097/rct.0000000000001459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/08/2023]
Abstract
OBJECTIVE This study aimed to compare computed tomography (CT) findings between patients with severe and nonsevere acute alcoholic hepatitis (AAH). METHODS We included 96 patients diagnosed with AAH between January 2011 and October 2021 who underwent 4-phase liver CT and laboratory blood tests. Two radiologists reviewed the initial CT images with respect to distribution and grade of hepatic steatosis; transient parenchymal arterial enhancement (TPAE); and presence of cirrhosis, ascites, and hepatosplenomegaly. A Maddrey discriminant function score (4.6 × [patient's prothrombin time - control] + total bilirubin [mg/mL]) was used as cutoff indicator for severity, with a score of 32 or higher indicating severe disease. The image findings were compared between the severe (n = 24) and nonsevere (n = 72) groups using the χ2 test or Fisher exact test. After univariate analysis, the most significant factor was identified using a logistic regression analysis. RESULTS In the univariate analysis, there were significant between-group differences in the TPAE, liver cirrhosis, splenomegaly, and ascites (P < 0.0001, P < 0.0001, P = 0.0002, and P = 0.0163, respectively). Among them, TPAE was the only significant factor for severe AAH (P < 0.0001; odds ratio, 48.1; 95% confidence interval, 8.3-280.6). Using this single indicator, the estimated accuracy, positive predictive, and negative predictive values were 86%, 67%, and 97%, respectively. CONCLUSIONS Transient parenchymal arterial enhancement was the only significant CT finding in severe AAH.
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13
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Idalsoaga F, Ayares G, Díaz LA, Arnold J, Ayala-Valverde M, Hudson D, Arrese M, Arab JP. Current and emerging therapies for alcohol-associated hepatitis. LIVER RESEARCH (BEIJING, CHINA) 2023; 7:35-46. [PMID: 39959695 PMCID: PMC11792060 DOI: 10.1016/j.livres.2023.03.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Revised: 01/16/2023] [Accepted: 03/07/2023] [Indexed: 03/17/2023]
Abstract
Alcohol-related liver disease (ALD) encompasses a spectrum of diseases caused by excessive alcohol consumption. ALD includes hepatic steatosis, steatohepatitis, variable degrees of fibrosis, cirrhosis, and alcohol-associated hepatitis (AH), the latter being the most severe acute form of the disease. Severe AH is associated with high mortality (reaching up to 30%-50%) at 90 days. The cornerstone of ALD, and particularly AH, treatment continues to be abstinence, accompanied by support measures such as nutritional supplementation and management of alcohol withdrawal syndrome (AWS). In severe AH with model for end-stage liver disease (MELD) score ≥21, corticosteroids can be used, especially MELD score between 25 and 39, where the highest benefit is achieved. Other key aspects of treatment include the early identification of infections and their associated management and the proper identification of potential candidates for liver transplantation. The development of new therapies based on the pathophysiology and mechanisms of liver injury are underway. This includes the modulation and management of the innate immune response, gut dysbiosis, bacterial translocation, and bacteria-derived products from the intestine. These hold promise for the future of AH treatment.
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Affiliation(s)
- Francisco Idalsoaga
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Gustavo Ayares
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis Antonio Díaz
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jorge Arnold
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - María Ayala-Valverde
- Internal Medicine Service, Hospital El Pino, Critical Patient Unit, Clinica Davila, Santiago, Chile
| | - David Hudson
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
| | - Marco Arrese
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan Pablo Arab
- Department of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
- Department of Epidemiology and Biostatistics, Schulich School of Medicine, Western University, London, Ontario, Canada
- Alimentiv, London, Ontario, Canada
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14
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Thakral N, Deutsch-Link S, Singal AK. Therapeutic Pipeline in Alcohol-Associated Liver Disease. Semin Liver Dis 2023; 43:60-76. [PMID: 36572032 PMCID: PMC11503467 DOI: 10.1055/s-0042-1759614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Alcohol-associated liver disease is a leading cause of mortality and morbidity worldwide. Patients with alcohol-associated liver disease are often diagnosed at advanced stage and disease spectrum including alcoholic hepatitis, a severe manifestation with a high short-term mortality. Corticosteroid, recommended first-line treatment for patients with alcoholic hepatitis, is a very suboptimal treatment. Although the use of early liver transplantation has increased with consistent benefit in select patients with alcoholic hepatitis, its use remains heterogeneous worldwide due to lack of uniform selection criteria. Over the last decade, several therapeutic targets have evolved of promise with ongoing clinical trials in patients with cirrhosis and alcoholic hepatitis. Even with availability of effective medical therapies for alcohol-associated liver disease, long-term outcome depends on abstinence from alcohol use in any spectrum of alcohol-associated liver disease. However, alcohol use disorder treatment remains underutilized due to several barriers even in patients with advanced disease. There is an urgent unmet need to implement and promote integrated multidisciplinary care model with hepatologists and addiction experts to provide comprehensive management for these patients. In this review, we will discuss newer therapies targeting liver disease and therapies targeting alcohol use disorder in patients with alcohol-associated liver disease.
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Affiliation(s)
- Nimish Thakral
- Division of Gastroenterology and Hepatology, University of Kentucky, Lexington, Kentucky
| | - Sasha Deutsch-Link
- Department of Medicine, University of North Carolina at Chapel Hill, North Carolina
| | - Ashwani K. Singal
- Department of Medicine, University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota
- Division of Transplant Hepatology, Avera Transplant Institute, Sioux Falls, South Dakota
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Xu HY, Jiao YH, Li SY, Zhu X, Wang S, Zhang YY, Wei YJ, Shen YJ, Wang W, Shen YX, Shao JT. Hepatocyte-derived MANF mitigates ethanol-induced liver steatosis in mice via enhancing ASS1 activity and activating AMPK pathway. Acta Pharmacol Sin 2023; 44:157-168. [PMID: 35655095 DOI: 10.1038/s41401-022-00920-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 05/05/2022] [Indexed: 02/06/2023]
Abstract
Hepatic steatosis plays a detrimental role in the onset and progression of alcohol-associated liver disease (ALD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved protein related to the unfolded protein response. Recent studies have demonstrated that MANF plays an important role in liver diseases. In this study, we investigated the role of MANF in ethanol-induced steatosis and the underlying mechanisms. We showed that the hepatic MANF expression was markedly upregulated in mouse model of ALD by chronic-plus-single-binge ethanol feeding. Moreover, after chronic-plus-binge ethanol feeding, hepatocyte-specific MANF knockout (HKO) mice displayed more severe hepatic steatosis and liver injury than wild-type (WT) control mice. Immunoprecipitation-coupled MS proteomic analysis revealed that arginosuccinate synthase 1 (ASS1), a rate-limiting enzyme in the urea cycle, resided in the same immunoprecipitated complex with MANF. Hepatocyte-specific MANF knockout led to decreased ASS1 activity, whereas overexpression of MANF contributed to enhanced ASS1 activity in vitro. In addition, HKO mice displayed unique urea cycle metabolite patterns in the liver with elevated ammonia accumulation after ethanol feeding. ASS1 is known to activate AMPK by generating an intracellular pool of AMP from the urea cycle. We also found that MANF supplementation significantly ameliorated ethanol-induced steatosis in vivo and in vitro by activating the AMPK signaling pathway, which was partly ASS1 dependent. This study demonstrates a new mechanism in which MANF acts as a key molecule in maintaining hepatic lipid homeostasis by enhancing ASS1 activity and uncovers an interesting link between lipid metabolism and the hepatic urea cycle under excessive alcohol exposure.
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Affiliation(s)
- Han-Yang Xu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yan-Hong Jiao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Shi-Yu Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Xu Zhu
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Sheng Wang
- Center for Scientific Research of Anhui Medical University, Hefei, 230032, China
| | - Yu-Yang Zhang
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yi-Jun Wei
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Yu-Jun Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China
| | - Wei Wang
- Department of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital of Anhui Medical University, Hefei, 230022, China
| | - Yu-Xian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.
| | - Jun-Tang Shao
- School of Basic Medical Sciences, Anhui Medical University, Hefei, 230032, China.
- Biopharmaceutical Institute, Anhui Medical University, Hefei, 230032, China.
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Wakil A, Niazi M, Meybodi MA, Pyrsopoulos NT. Emerging Pharmacotherapies in Alcohol-Associated Hepatitis. J Clin Exp Hepatol 2023; 13:116-126. [PMID: 36647403 PMCID: PMC9840076 DOI: 10.1016/j.jceh.2022.06.012] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Accepted: 06/25/2022] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED The incidence of alcoholic-associated hepatitis (AH) is increasing. The treatment options for severe AH (sAH) are scarce and limited to corticosteroid therapy which showed limited mortality benefit in short-term use only. Therefore, there is a dire need for developing safe and effective therapies for patients with sAH and to improve their high mortality rates.This review article focuses on the current novel therapeutics targeting various mechanisms in the pathogenesis of alcohol-related hepatitis. Anti-inflammatory agents such as IL-1 inhibitor, Pan-caspase inhibitor, Apoptosis signal-regulating kinase-1, and CCL2 inhibitors are under investigation. Other group of agents include gut-liver axis modulators, hepatic regeneration, antioxidants, and Epigenic modulators. We describe the ongoing clinical trials of some of the new agents for alcohol-related hepatitis. CONCLUSION A combination of therapies was investigated, possibly providing a synergistic effect of drugs with different mechanisms. Multiple clinical trials of novel therapies in AH remain ongoing. Their result could potentially make a difference in the clinical course of the disease. DUR-928 and granulocyte colony-stimulating factor had promising results and further trials are ongoing to evaluate their efficacy in the large patient sample.
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Key Words
- AH, alcohol-Associated hepatitis
- ALD, Alcohol-associated liver disease
- ASK-1, Apoptosis signal-regulating kinase-1
- AUD, alcohol use disorder
- CCL2, C–C chemokine ligand type 2
- CVC, Cenicriviroc
- ELAD, Extracorporeal liver assist device
- FMT, Fecal Microbiota Transplant
- G-CSF, Granulocyte colony-stimulating factor
- HA35, Hyaluronic Acid 35KD
- IL-1, interleukin 1
- IL-6, interleukin 6
- LCFA, saturated long-chain fatty acids
- LDL, low-density lipoprotein cholesterol
- LPS, Lipopolysaccharides
- MCP-1, monocyte chemoattractant protein −1
- MDF, Maddrey's discriminant function
- MELD, Model for end-stage disease
- NAC, N-acetylcysteine
- NLRs, nucleotide-binding oligomerization domain-like receptors
- PAMPs, Pathogen-associated molecular patterns
- RCT, Randomized controlled trial
- SAM, S-Adenosyl methionine
- SCFA, short-chain fatty acids. 5
- TLRs, Toll-like receptors
- TNF, tumor necrotic factor
- alcohol-associated hepatitis
- anti-inflammatory
- antioxidants
- liver-gut axis
- microbiome
- sAH, severe alcohol-associated hepatitis
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Affiliation(s)
- Ali Wakil
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, New York, New Jersey, USA
| | - Mumtaz Niazi
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, New York, New Jersey, USA
| | - Mohamad A. Meybodi
- Department of Internal Medicine, Rutgers New Jersey Medical School, New York, New Jersey, USA
| | - Nikolaos T. Pyrsopoulos
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, New York, New Jersey, USA
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Outnumbered: Control Prothrombin Time in Maddrey's Discriminant Function Impacts Steroid Use but Not Mortality in Alcoholic Hepatitis. BIOLOGY 2022; 11:biology11121833. [PMID: 36552342 PMCID: PMC9775026 DOI: 10.3390/biology11121833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 12/08/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND AND AIMS In alcoholic hepatitis (AH), increases in the total bilirubin (TB) and the prothrombin time (PT), which are included in the Maddrey's discriminant function (MDF) and the model for end-stage liver disease (MELD), are associated with poor outcomes. However, the impact of which control PT in the MDF to use compared to the MELD on the outcomes in AH is unknown. Our aim is to determine whether the choice of the control PT used in the MDF calculations has any impact on steroid use and survival when compared to the MELD in those with AH. METHODS Through retrospective chart review, we analyzed 882 subjects who were admitted from 2012 to 2020 with acute AH. Their MDF was calculated [(TB + 4.6 × (PT-control)] using the following three different control PTs: 12, 13.5, and 14.8 s, and was compared to the MELD. The primary outcomes were steroid use and 30-day survival. RESULTS When it was stratified by the control PT, the percentage of MDF ≥ 32 (the threshold for steroids) decreased with increasing control PT (70%, 61%, and 52%, respectively), along with decreased steroid use (91%, 84%, and 75%, respectively). Those who received steroids were not shown to have improved 30-day survival compared to those who did not receive steroids (p = 0.41). The ability of the MDF for each control PT threshold to predict 30-day survival was similar (AUROC 0.735), and was lower compared to the MELD (0.767). CONCLUSION While the choice of PT control in the MDF impacted the use of steroids in AH, the use of steroids and the choice of PT control used did not impact the overall survival. Regardless of which control PT was used in the MDF, the MELD was better at predicting 30-day survival. Important information: Background: Treatment with steroids is indicated in alcoholic hepatitis (AH) with Maddrey discriminant function (MDF) ≥ 32 and the model for end-stage liver disease (MELD) ≥ 20. The impact that the control prothrombin time (PT) value that is used in MDF has on steroid use and survival in AH is poorly understood. FINDINGS The choice of control PT that is used when calculating the MDF impacts the use of steroids but does not impact mortality. The MELD was better than the MDF at any control PT used in predicting survival in acute AH. IMPLICATIONS FOR PATIENT CARE Providers should be aware that higher control PT's have an effect on treatment decisions but should not generally impact survival in this population. The MELD appears to better predict 30-day survival in this population.
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Wakil A, Mohamed M, Tafesh Z, Niazi M, Olivo R, Xia W, Greenberg P, Pyrsopoulos N. Trends in hospitalization for alcoholic hepatitis from 2011 to 2017: A USA nationwide study. World J Gastroenterol 2022; 28:5036-5046. [PMID: 36160652 PMCID: PMC9494933 DOI: 10.3748/wjg.v28.i34.5036] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/01/2022] [Accepted: 07/25/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe alcoholic hepatitis (AH) is one of the most lethal manifestations of alcohol-associated liver disease. In light of the increase in alcohol consumption worldwide, the incidence of AH is on the rise, and data examining the trends of AH admission is needed. AIM To examine inpatient admission trends secondary to AH, along with their clinical outcomes and epidemiological characteristics. METHODS The National Inpatient Sample (NIS) database was utilized, and data from 2011 to 2017 were reviewed. We included individuals aged ≥ 21 years who were admitted with a primary or secondary diagnosis of AH using the International Classification of Diseases (ICD)-9 and its correspondent ICD-10 codes. Hepatitis not related to alcohol was excluded. The national estimates of inpatient admissions were obtained using sample weights provided by the NIS. RESULTS AH-related hospitalization demonstrated a significant increase in the USA from 281506 (0.7% of the total admission in 2011) to 324050 (0.9% of the total admission in 2017). The median age was 54 years. The most common age group was 45-65 years (range 57.8%-60.7%). The most common race was white (63.2%-66.4%), and patients were predominantly male (69.7%-71.2%). The primary healthcare payers were Medicare (29.4%-30.7%) and Medicaid (21.5%-32.5%). The most common geographical location was the Southern USA (33.6%-34.4%). Most patients were admitted to a tertiary care center (50.2%-62.3%) located in urban areas. Mortality of AH in this inpatient sample was 5.3% in 2011 and 5.5% in 2017. The most common mortality-associated risk factors were acute renal failure (59.6%-72.1%) and gastrointestinal hemorrhage (17.2%-20.3%). The total charges were noted to range between $25242.62 and $34874.50. CONCLUSION The number of AH inpatient hospitalizations significantly increased from 2011 to 2017. This could have a substantial financial impact with increasing healthcare costs and utilization. AH-mortality remained the same.
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Affiliation(s)
- Ali Wakil
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Mujtaba Mohamed
- Department of Gastroenterology and Hepatology, Marshall University Hospital, Huntington, WV 25701, USA
| | - Zaid Tafesh
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Mumtaz Niazi
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Raquel Olivo
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
| | - Weiyi Xia
- Department of Biostatistics & Epidemiology, Rutgers School of Public Health, Piscataway, NJ 08854, USA
| | - Patricia Greenberg
- Department of Biostatistics & Epidemiology, Rutgers School of Public Health, Piscataway, NJ 08854, USA
| | - Nikolaos Pyrsopoulos
- Department of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, USA
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Ayares G, Idalsoaga F, Díaz LA, Arnold J, Arab JP. Current Medical Treatment for Alcohol-Associated Liver Disease. J Clin Exp Hepatol 2022; 12:1333-1348. [PMID: 36157148 PMCID: PMC9499849 DOI: 10.1016/j.jceh.2022.02.001] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 02/06/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol-associated liver disease is one of the main causes of chronic liver disease. It comprises a clinical-histologic spectrum of presentations, from steatosis, steatohepatitis, to different degrees of fibrosis, including cirrhosis and severe necroinflammatory disease, called alcohol-associated hepatitis. In this focused update, we aim to present specific therapeutic interventions and strategies for the management of alcohol-associated liver disease. Current evidence for management in all spectra of manifestations is derived from general chronic liver disease recommendations, but with a higher emphasis on abstinence and nutritional support. Abstinence should comprise the treatment of alcohol use disorder as well as withdrawal syndrome. Nutritional assessment should also consider the presence of sarcopenia and its clinical manifestation, frailty. The degree of compensation of the disease should be evaluated, and complications, actively sought. The most severe acute form of this disease is alcohol-associated hepatitis, which has high mortality and morbidity. Current treatment is based on corticosteroids that act by reducing immune activation and blocking cytotoxicity and inflammation pathways. Other aspects of treatment include preventing and treating hepatorenal syndrome as well as preventing infections although there is no clear evidence as to the benefit of probiotics and antibiotics in prophylaxis. Novel therapies for alcohol-associated hepatitis include metadoxine, interleukin-22 analogs, and interleukin-1-beta antagonists. Finally, granulocyte colony-stimulating factor, microbiota transplantation, and gut-liver axis modulation have shown promising results. We also discuss palliative care in advanced alcohol-associated liver disease.
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Key Words
- AC, Amoxicillin/clavulanate
- ACLF, Acute-on-Chronic Liver Failure
- ADLs, Activities of Daily Living
- AH, Alcohol-Associated Hepatitis
- AKI-HRS, Acute Kidney Injury - Hepatorenal Syndrome
- ALD
- ALD, Alcohol-Associated Liver Disease
- ASH, Alcoholic Steatohepatitis
- AUD, Alcohol Use Disorder
- AWS, Alcohol Withdrawal Syndrome
- BCAAs, Branched-Chain Amino Acids
- CDC, Center for Disease Control
- CI, Confidence Interval
- COVID-19, Coronavirus Disease 2019
- CT, Computerized Tomography
- GABA, gamma-aminobutyric acid agonist
- HBV, Hepatitis B Virus
- HCC, Hepatocellular Carcinoma
- HCV, Hepatitis C Virus
- HE, Hepatic Encephalopathy
- HIV, Human Immunodeficiency Virus
- HR, Hazard Ratio
- IBW, Ideal Body Weight
- ICA, International Club of Ascites
- IL-1β, Interleukin-1β
- IL-22, Interleukin-22
- KPS, Karnofsky Performance Status
- LB, Liver Biopsy
- LPS, Lipopolysaccharide
- LSM, Liver Stiffness Measurement
- LT, Liver Transplantation
- MDF, Maddrey’s Discriminant Function
- MELD, Model of End-Stage Liver Disease
- MRI, Magnetic Resonance Imaging
- MUST, Malnutrition Universal Screening Tool
- NIAAA, National Institute on Alcohol Abuse and Alcoholism
- NRS-2002, Nutritional Risk Screening-2002
- OR, Odds Ratio
- PAMPs, Pathogen-Activated Molecular Patterns
- PMI, Psoas Muscle Index
- PTX, Pentoxifylline
- RAI, Relative Adrenal Insufficiency
- RCT, Randomized Clinical Trials
- RFH-NPT, Royal Free Hospital-Nutritional Prioritizing Tool
- ROS, Reactive Oxygen Species
- RR, Relative Risk
- SIRS, Systemic Inflammatory Response Syndrome
- TNF, Tumor Necrosis Factor
- WKS, Wernicke-Korsakoff Syndrome
- alcohol
- alcohol use disorders
- alcohol-associated hepatitis
- cirrhosis
- fatty liver disease
- steatosis
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Affiliation(s)
- Gustavo Ayares
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Francisco Idalsoaga
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Luis A. Díaz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Jorge Arnold
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Juan P. Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
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Cho Y, Joshi R, Lowe P, Copeland C, Ribeiro M, Morel C, Catalano D, Szabo G. Granulocyte colony-stimulating factor attenuates liver damage by M2 macrophage polarization and hepatocyte proliferation in alcoholic hepatitis in mice. Hepatol Commun 2022; 6:2322-2339. [PMID: 35997009 PMCID: PMC9426408 DOI: 10.1002/hep4.1925] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/21/2021] [Accepted: 01/22/2022] [Indexed: 11/10/2022] Open
Abstract
Massive inflammation and liver failure are main contributors to the high mortality in alcohol-associated hepatitis (AH). In recent clinical trials, granulocyte colony-stimulating factor (G-CSF) therapy improved liver function and survival in patients with AH. However, the mechanisms of G-CSF-mediated beneficial effects in AH remain elusive. In this study, we evaluated effects of in vivo G-CSF administration, using a mouse model of AH. G-CSF treatment significantly reduced liver damage in alcohol-fed mice even though it increased the numbers of liver-infiltrating immune cells, including neutrophils and inflammatory monocytes. Moreover, G-CSF promoted macrophage polarization toward an M2-like phenotype and increased hepatocyte proliferation, which was indicated by an increased Ki67-positive signal colocalized with hepatocyte nuclear factor 4 alpha (HNF-4α) and cyclin D1 expression in hepatocytes. We found that G-CSF increased G-CSF receptor expression and resulted in reduced levels of phosphorylated β-catenin in hepatocytes. In the presence of an additional pathogen-associated molecule, lipopolysaccharide (LPS), which is significantly increased in the circulation and liver of patients with AH, the G-CSF-induced hepatoprotective effects were abolished in alcohol-fed mice. We still observed increased Ki67-positive signals in alcohol-fed mice following G-CSF treatment; however, Ki67 and HNF-4α did not colocalize in LPS-challenged mice. Conclusion: G-CSF treatment increases immune cell populations, particularly neutrophil counts, and promotes M2-like macrophage differentiation in the liver. More importantly, G-CSF treatment reduces alcohol-induced liver injury and promotes hepatocyte proliferation in alcohol-fed mice. These data provide new insights into the understanding of mechanisms mediated by G-CSF and its therapeutic effects in AH.
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Affiliation(s)
- Yeonhee Cho
- Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterMassachusettsUSA
- Department of MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Radhika Joshi
- Department of MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Patrick Lowe
- Emergency MedicineMassachusetts General HospitalBrigham & Women’s HospitalBostonMassachusettsUSA
| | - Christopher Copeland
- Department of MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMassachusettsUSA
| | - Marcelle Ribeiro
- Department of MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMassachusettsUSA
| | | | - Donna Catalano
- Department of MedicineUniversity of Massachusetts Medical SchoolWorcesterMassachusettsUSA
| | - Gyongyi Szabo
- Department of MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBostonMassachusettsUSA
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21
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Han HT, Jin WL, Li X. Mesenchymal stem cells-based therapy in liver diseases. MOLECULAR BIOMEDICINE 2022; 3:23. [PMID: 35895169 PMCID: PMC9326420 DOI: 10.1186/s43556-022-00088-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/20/2022] [Indexed: 12/24/2022] Open
Abstract
Multiple immune cells and their products in the liver together form a complex and unique immune microenvironment, and preclinical models have demonstrated the importance of imbalances in the hepatic immune microenvironment in liver inflammatory diseases and immunocompromised liver diseases. Various immunotherapies have been attempted to modulate the hepatic immune microenvironment for the purpose of treating liver diseases. Mesenchymal stem cells (MSCs) have a comprehensive and plastic immunomodulatory capacity. On the one hand, they have been tried for the treatment of inflammatory liver diseases because of their excellent immunosuppressive capacity; On the other hand, MSCs have immune-enhancing properties in immunocompromised settings and can be modified into cellular carriers for targeted transport of immune enhancers by genetic modification, physical and chemical loading, and thus they are also used in the treatment of immunocompromised liver diseases such as chronic viral infections and hepatocellular carcinoma. In this review, we discuss the immunological basis and recent strategies of MSCs for the treatment of the aforementioned liver diseases. Specifically, we update the immune microenvironment of the liver and summarize the distinct mechanisms of immune microenvironment imbalance in inflammatory diseases and immunocompromised liver diseases, and how MSCs can fully exploit their immunotherapeutic role in liver diseases with both immune imbalance patterns.
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Affiliation(s)
- Heng-Tong Han
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
| | - Wei-Lin Jin
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, 730000, P. R, China.
- Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, No. 1 West Donggang Road, Lanzhou, 730000, People's Republic of China.
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, People's Republic of China.
- Key Laboratory Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, 730000, People's Republic of China.
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22
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Luther J, Vannier AG, Schaefer EA, Goodman RP. The circulating proteomic signature of alcohol-associated liver disease. JCI Insight 2022; 7:e159775. [PMID: 35866482 PMCID: PMC9431701 DOI: 10.1172/jci.insight.159775] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
Despite being a leading cause of advanced liver disease, alcohol-associated liver disease (ALD) has no effective medical therapies. The circulating proteome, which comprises proteins secreted by different cells and tissues in the context of normal physiological function or in the setting of disease and illness, represents an attractive target for uncovering novel biology related to the pathogenesis of ALD. In this work, we used the aptamer-based SomaScan proteomics platform to quantify the relative concentration of over 1300 proteins in a well-characterized cohort of patients with the spectrum of ALD. We found a distinct circulating proteomic signature that correlated with ALD severity, including over 600 proteins that differed significantly between ALD stages, many of which have not previously been associated with ALD to our knowledge. Notably, certain proteins that were markedly dysregulated in patients with alcohol-associated hepatitis were also altered, to a lesser degree, in patients with subclinical ALD and may represent early biomarkers for disease progression. Taken together, our work highlights the vast and distinct changes in the circulating proteome across the wide spectrum of ALD, identifies potentially novel biomarkers and therapeutic targets, and provides a proteomic resource atlas for ALD researchers and clinicians.
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23
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Yen YT, Park JH, Kang SH, Su T, Cheng H, Wen WC, Lin SS, Tai YL, Chen PN, Tsai SC. Clinical Benefits of Golden-Antrodia Camphorata Containing Antroquinonol in Liver Protection and Liver Fat Reduction After Alcoholic Hepatitis. Front Pharmacol 2022; 13:757494. [PMID: 35800453 PMCID: PMC9253287 DOI: 10.3389/fphar.2022.757494] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 05/30/2022] [Indexed: 12/12/2022] Open
Abstract
Objective: It has been reported that antroquinonol extracted from Golden-Antrodia camphorate exerts protective effects on liver function both in vitro and in vivo. However, the protective effects of Golden-Antrodia camphorata on liver function have not been fully investigated in human clinical studies. Therefore, the present study aimed to evaluate the beneficial effects of Golden-Antrodia camphorata on hepatic function after alcohol consumption in human subjects. Methods: A total of 80 participants with increased γ-glutamyl transferase levels (60–180 U/L) were enrolled in the current study and were randomly divided into two groups. Participants in the first group were orally administrated with 300 mg/day Golden-Antrodia camphorata (tablets), while those in the second group received placebo tablets for 12 weeks. Biochemical routine blood tests were performed at 6 and 12 weeks following the first administration. Results: At 12 weeks post the first Golden-Antrodia camphorata administration, the serum levels of aspartate aminotransferase (AST; p < 0.0001), alanine aminotransferase (ALT; p = 0.0002) and triglyceride (p = 0.0158) were notably declined in the Golden-Antrodia camphorata treatment group compared with the placebo group. No clinically significant differences were observed between the Golden-Antrodia camphorata treatment and placebo groups in terms of general safety parameters. Conclusion: A statistically significant difference was obtained in the serum levels of AST, ALT and triglycerides between the Golden-Antrodia camphorata and placebo groups. However, no clinical significance was observed in any of the safety parameters examined. Overall, these findings indicated that treatment with Golden-Antrodia camphorata exerted protective effects on liver function.
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Affiliation(s)
- Yu-Ting Yen
- Drug Development Center, Institute of New Drug Development, Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
| | - Joo-Hyun Park
- Department of Family Medicine, Korea University Ansan Hospital, Korea University College of Medicine, Ansan, South Korea
| | - Seung-Hyun Kang
- Clinical Research Center of H PLUS Yangji Hospital, Seoul, South Korea
| | - Today Su
- Golden Biotechnology Corporation, New Taipei City, Taiwan
| | - Howard Cheng
- Golden Biotechnology Corporation, New Taipei City, Taiwan
| | - Wu-Che Wen
- Golden Biotechnology Corporation, New Taipei City, Taiwan
| | - Shin-Shiou Lin
- Golden Biotechnology Corporation, New Taipei City, Taiwan
| | - Yu-Ling Tai
- Golden Biotechnology Corporation, New Taipei City, Taiwan
| | - Pei-Ni Chen
- Golden Biotechnology Corporation, New Taipei City, Taiwan
- *Correspondence: Pei-Ni Chen, ; Shih-Chang Tsai,
| | - Shih-Chang Tsai
- Department of Biological Science and Technology, China Medical University, Taichung, Taiwan
- *Correspondence: Pei-Ni Chen, ; Shih-Chang Tsai,
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24
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Jiménez C, Ventura-Cots M, Sala M, Calafat M, Garcia-Retortillo M, Cirera I, Cañete N, Soriano G, Poca M, Simón-Talero M, Altamirano J, Lucey M, Garcia-Tsao G, Brown RS, Schwabe RF, Verna EC, Schnabl B, Bosques-Padilla F, Mathurin P, Caballería J, Louvet A, Shawcross DL, Abraldes JG, Genescà J, Bataller R, Vargas V. Effect of rifaximin on infections, acute-on-chronic liver failure and mortality in alcoholic hepatitis: A pilot study (RIFA-AH). Liver Int 2022; 42:1109-1120. [PMID: 35220659 PMCID: PMC9311407 DOI: 10.1111/liv.15207] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 01/31/2022] [Accepted: 02/15/2022] [Indexed: 01/26/2023]
Abstract
BACKGROUND & AIMS Alcoholic hepatitis (AH) is associated with a high incidence of infection and mortality. Rifaximin reduces bacterial overgrowth and translocation. We aimed to study whether the administration of rifaximin as an adjuvant treatment to corticosteroids decreases the number of bacterial infections at 90 days in patients with severe AH compared to a control cohort. METHODS This was a multicentre, open, comparative pilot study of the addition of rifaximin (1200 mg/day/90 days) to the standard treatment for severe AH. The results were compared with a carefully matched historical cohort of patients treated with standard therapy and matching by age and model of end-stage liver disease (MELD). We evaluated bacterial infections, liver-related complications, mortality and liver function tests after 90 days. RESULTS Twenty-one and 42 patients were included in the rifaximin and control groups respectively. No significant baseline differences were found between groups. The mean number of infections per patient was 0.29 and 0.62 in the rifaximin and control groups, respectively (p = .049), with a lower incidence of acute-on-chronic liver failure (ACLF) linked to infections within the treatment group. Liver-related complications were lower within the rifaximin group (0.43 vs. 1.26 complications/patient respectively) (p = .01). Mortality was lower in the treated versus the control groups (14.2% vs. 30.9, p = .15) without significant differences. No serious adverse events were associated with rifaximin treatment. CONCLUSIONS Rifaximin is safe in severe AH with a significant reduction in clinical complications. A lower number of infections and a trend towards a lower ACLF and mortality favours its use in these patients.
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Affiliation(s)
- César Jiménez
- Vall d'Hebron Hospital Universitari, Liver Unit; Vall d'Hebron Institut de Recerca, Liver Unit, Universitat Autonoma de Barcelona, Department of Medicine, Barcelona, Spain
| | - Meritxell Ventura-Cots
- Vall d'Hebron Hospital Universitari, Liver Unit; Vall d'Hebron Institut de Recerca, Liver Unit, Universitat Autonoma de Barcelona, Department of Medicine, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Margarita Sala
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Gastroenterology Department, Hospital Universitari Germans Trias I Pujol, Badalona, Spain
| | - Margalida Calafat
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Gastroenterology Department, Hospital Universitari Germans Trias I Pujol, Badalona, Spain
| | - Montserrat Garcia-Retortillo
- Liver Section, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Isabel Cirera
- Liver Section, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Nuria Cañete
- Liver Section, Gastroenterology Department, Hospital del Mar, IMIM (Hospital del Mar Medical Research Institute), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - Germán Soriano
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Department of Gastroenterology Hospital de la Santa Creu i Sant Pau Barcelona Spain, Institut d'Investigació Biomèdica Sant Pau IIB Sant Pau, Gastroenterology, Barcelona, Catalunya, ES, Universitat Autonoma de Barcelona, Medicine, Barcelona, Catalunya, Spain
| | - María Poca
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Department of Gastroenterology Hospital de la Santa Creu i Sant Pau Barcelona Spain, Institut d'Investigació Biomèdica Sant Pau IIB Sant Pau, Gastroenterology, Barcelona, Catalunya, ES, Universitat Autonoma de Barcelona, Medicine, Barcelona, Catalunya, Spain
| | - Macarena Simón-Talero
- Vall d'Hebron Hospital Universitari, Liver Unit; Vall d'Hebron Institut de Recerca, Liver Unit, Universitat Autonoma de Barcelona, Department of Medicine, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - José Altamirano
- Department of Internal Medicine, Hospital Quironsalud, Barcelona, Spain
| | - Michael Lucey
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University, New Haven, Connecticut Section of Digestive Diseases, Department of Veterans Affairs Connecticut Healthcare, West Haven, Connecticut, USA
| | - Robert S Brown
- Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York City, New York, USA
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York City, New York, USA
| | - Elizabeth C Verna
- Center for Liver Disease and Transplantation, Columbia University Irving Medical Center, New York City, New York, USA
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | | | - Philippe Mathurin
- Service des Maladies de L'appareil Digestif et Unité INSERM U995, Lille, France
| | - Juan Caballería
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Liver Unit, Hospital Clinic, Barcelona, Spain
| | - Alexandre Louvet
- Service des Maladies de L'appareil Digestif et Unité INSERM U995, Lille, France
| | - Debbie L Shawcross
- Department of Inflammation Biology, School of Immunology and Microbial Sciences, Institute of Liver Sciences, King's College London, London, UK
| | - Juan G Abraldes
- Division of Gastroenterology, Liver Unit, University of Alberta, Edmonton, Canada
| | - Joan Genescà
- Vall d'Hebron Hospital Universitari, Liver Unit; Vall d'Hebron Institut de Recerca, Liver Unit, Universitat Autonoma de Barcelona, Department of Medicine, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
| | - Ramon Bataller
- Center for Liver Diseases, Pittsburgh Liver Research Center, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Víctor Vargas
- Vall d'Hebron Hospital Universitari, Liver Unit; Vall d'Hebron Institut de Recerca, Liver Unit, Universitat Autonoma de Barcelona, Department of Medicine, Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
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25
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Luo J, Zhang J, Lai W, Wang S, Zhou L, Shi Y, Ba J, Hu J, Wang Y, Li L, Wu BQ. Disseminated Human Parvovirus B19 Infection Induced Multiple Organ Dysfunction Syndrome in an Adult Patient With Alcoholic Hepatitis Complicated by Hemolytic Anemia: A Case Report and Literature Review. Front Immunol 2021; 12:742990. [PMID: 34970255 PMCID: PMC8712433 DOI: 10.3389/fimmu.2021.742990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
BackgroundHuman parvovirus B19 (B19) can cause acute hepatitis and is attributed to the high mortality of alcoholic hepatitis (AH). B19 infection is generally self-healing in previously healthy people, but it can cause fatal effects in some high-risk groups and increase its virulence and infectivity. Disseminated B19 infection-induced multiple organ dysfunction syndrome (MODS) in patients with AH has not been reported yet. Here, we described B19 viremia in an adult patient with AH accompanied by hemolytic anemia (HA), leading to disseminated infection and secondary MODS, as well as self-limiting B19 infections in seven nurses caring for him. Meanwhile, we reviewed the literature on AH and B19 infection.Case PresentationA 43-year-old male patient with AH accompanied by HA was transferred to the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China, on March 31, 2021. After supportive treatment, his transaminase and bilirubin levels were reduced, but his anemia worsened. He received a red blood cell (RBC) infusion on April 9 for hemoglobin (Hb) lower than 6 g/dl. On April 13, he suddenly had a high fever. Under empirical anti-infection, his high fever dropped and maintained at a low fever level; however, his anemia worsened. On April 25, he was transferred to the medical intensive care unit (MICU) due to severe pneumonia, acute respiratory distress syndrome (ARDS), acute aplastic crisis (AAC), and hemophagocytic syndrome (HPS), which were subsequently confirmed to be related to B19 infection. After methylprednisolone, intravenous immunoglobulin (IVIG), empirical anti-infection, and supportive treatment, the lung infection improved, but hematopoietic and liver abnormalities aggravated, and systemic B19 infection occurred. Finally, the patient developed a refractory arrhythmia, heart failure, and shock and was referred to a local hospital by his family on May 8, 2021. Unfortunately, he died the next day. Fourteen days after he was transferred to MICU, seven nurses caring for him in his first two days in the MICU developed self-limiting erythema infectiosum (EI).ConclusionsB19 infection is self-limiting in healthy people, with low virulence and infectivity; however, in AH patients with HA, it can lead to fatal consequences and high contagion.
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Affiliation(s)
- Jinmei Luo
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jingcong Zhang
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wenxing Lai
- Division of Hematology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shaofang Wang
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Laizhi Zhou
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yunfeng Shi
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Junhui Ba
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Jiajia Hu
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanhong Wang
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Laisheng Li
- Department of Laboratory Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Ben-Quan Wu
- Department of Internal Medicine, Medical Intensive Care Unit and Division of Respiratory Diseases, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Ben-Quan Wu,
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26
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Kang H, Kim MB, Park YK, Lee JY. A mouse model of the regression of alcoholic hepatitis: Monitoring the regression of hepatic steatosis, inflammation, oxidative stress, and NAD + metabolism upon alcohol withdrawal. J Nutr Biochem 2021; 99:108852. [PMID: 34525389 DOI: 10.1016/j.jnutbio.2021.108852] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 06/01/2021] [Accepted: 08/13/2021] [Indexed: 02/06/2023]
Abstract
This study aimed to develop a well-characterized mouse model of alcoholic hepatitis (AH) regression. Male C57BL/6J mice were fed a Lieber-DeCarli (LD) control diet or LD containing 5% ethanol for ten days followed by one binge, which is the chronic-binge model of AH developed by the National Institute on Alcohol Abuse and Alcoholism. To determine AH regression, mice previously exposed to ethanol were put on LD control diet and metabolic and inflammatory features were monitored weekly for three weeks. Serum alcohol, total cholesterol, and alanine transaminase levels were increased in ethanol-fed mice, which declined to those of no ethanol controls within one and three weeks after ethanol withdrawal, respectively. Serum malondialdehyde was increased with ethanol feeding, but it was restored to no ethanol control levels within one week. Ethanol-induced changes in the hepatic expression of genes involved in lipogenesis, fatty acid oxidation, ethanol metabolism, and antioxidant response were restored to those of no ethanol controls after 3 weeks of ethanol withdrawal. Also, ethanol-induced hepatic inflammation was gradually decreased during the 3 weeks of ethanol withdrawal. Hepatic nicotinamide adenine dinucleotide (NAD+) levels and the expression of enzymes involved in the NAD+ salvage pathway were decreased by ethanol feeding, which was mitigated after ethanol withdrawal. Ethanol significantly lowered hepatic sirtuin 1 expression, but its levels were restored with ethanol cessation. This study established a mouse model of AH regression, which can be used as a preclinical model to study the potential of dietary bioactives or therapeutic agents on AH regression.
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Affiliation(s)
- Hyunju Kang
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Mi-Bo Kim
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Young-Ki Park
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA
| | - Ji-Young Lee
- Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA.
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27
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Kim DH, Sim Y, Hwang JH, Kwun IS, Lim JH, Kim J, Kim JI, Baek MC, Akbar M, Seo W, Kim DK, Song BJ, Cho YE. Ellagic Acid Prevents Binge Alcohol-Induced Leaky Gut and Liver Injury through Inhibiting Gut Dysbiosis and Oxidative Stress. Antioxidants (Basel) 2021; 10:antiox10091386. [PMID: 34573017 PMCID: PMC8465052 DOI: 10.3390/antiox10091386] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) is a major liver disease worldwide and can range from simple steatosis or inflammation to fibrosis/cirrhosis, possibly through leaky gut and systemic endotoxemia. Many patients with alcoholic steatohepatitis (ASH) die within 60 days after clinical diagnosis due to the lack of an approved drug, and thus, synthetic and/or dietary agents to prevent ASH and premature deaths are urgently needed. We recently reported that a pharmacologically high dose of pomegranate extract prevented binge alcohol-induced gut leakiness and hepatic inflammation by suppressing oxidative and nitrative stress. Herein, we investigate whether a dietary antioxidant ellagic acid (EA) contained in many fruits, including pomegranate and vegetables, can protect against binge alcohol-induced leaky gut, endotoxemia, and liver inflammation. Pretreatment with a physiologically-relevant dose of EA for 14 days significantly reduced the binge alcohol-induced gut barrier dysfunction, endotoxemia, and inflammatory liver injury in mice by inhibiting gut dysbiosis and the elevated oxidative stress and apoptosis marker proteins. Pretreatment with EA significantly prevented the decreased amounts of gut tight junction/adherent junction proteins and the elevated gut leakiness in alcohol-exposed mice. Taken together, our results suggest that EA could be used as a dietary supplement for alcoholic hepatitis patients.
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Affiliation(s)
- Dong-ha Kim
- Department of Food and Nutrition, Andong National University, Andong 36729, Korea; (D.-h.K.); (Y.S.); (J.-h.H.); (I.-S.K.)
| | - Yejin Sim
- Department of Food and Nutrition, Andong National University, Andong 36729, Korea; (D.-h.K.); (Y.S.); (J.-h.H.); (I.-S.K.)
| | - Jin-hyeon Hwang
- Department of Food and Nutrition, Andong National University, Andong 36729, Korea; (D.-h.K.); (Y.S.); (J.-h.H.); (I.-S.K.)
| | - In-Sook Kwun
- Department of Food and Nutrition, Andong National University, Andong 36729, Korea; (D.-h.K.); (Y.S.); (J.-h.H.); (I.-S.K.)
| | - Jae-Hwan Lim
- Department of Biological Science, Andong National University, Andong 36729, Korea;
| | - Jihoon Kim
- Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA;
| | - Jee-In Kim
- Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
| | - Moon-Chang Baek
- Department of Molecular Medicine, School of Medicine, Cell & Matrix Research Institute, Kyungpook National University, Daegu 41944, Korea;
| | - Mohammed Akbar
- Division of Neuroscience and Behavior, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892, USA;
| | - Wonhyo Seo
- College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul 03760, Korea;
| | - Do-Kyun Kim
- Korea Zoonosis Research Institute, Jeonbuk National University, Iksan 54531, Korea;
| | - Byoung-Joon Song
- Section of Molecular Pharmacology and Toxicology, Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health Bethesda, Bethesda, MD 20892, USA
- Correspondence: (B.-J.S.); (Y.-E.C.)
| | - Young-Eun Cho
- Department of Food and Nutrition, Andong National University, Andong 36729, Korea; (D.-h.K.); (Y.S.); (J.-h.H.); (I.-S.K.)
- Correspondence: (B.-J.S.); (Y.-E.C.)
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Wang R, Mu J. Arbutin attenuates ethanol-induced acute hepatic injury by the modulation of oxidative stress and Nrf-2/HO-1 signaling pathway. J Biochem Mol Toxicol 2021; 35:e22872. [PMID: 34346143 DOI: 10.1002/jbt.22872] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 03/20/2021] [Accepted: 07/21/2021] [Indexed: 12/17/2022]
Abstract
Alcoholic liver disease (ALD) is a pervasive ailment due to the excessive consumption of alcohol and there is no operative drug for its treatment. The current exploration was intended to examine the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats via the modulation of the Nrf-2/HO-1 signaling cascade. Wistar rats were challenged with the 3 g/kg/day (40% v/v) of ethanol for 4 weeks to provoke the ALD and concomitantly supplemented with 40 mg/kg of arbutin. The liver function markers enzymes, inflammatory cytokines, and oxidative stress markers levels were scrutinized by using the respective assay kits. The mRNA expression of Nrf-2/HO-1 signaling proteins was studied by reverse-transcription polymerase chain reaction. The histological alterations of liver tissues were examined. HepG2 cells were used for the in vitro studies. The levels of oxidative stress markers and liver marker enzymes were examined by using kits. Reactive oxygen species (ROS) and apoptotic cell death was detected by using fluorescent staining. There were no major differences in the body weight and liver weight of experimental animals. Arbutin treatment appreciably reduced the liver marker enzymes, upregulated superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and the hydroxyl scavenging ability, and diminished the tumor necrosis factor-α and interleukin-6 levels in the serum of ethanol provoked animals. Arbutin triggered Nrf-2/HO-1 signaling cascade liver tissues of ethanol-provoked animals. Histological findings proved the preventing effects of arbutin. Arbutin did not demonstrate toxicity to the HepG2 cells. It reduced the aspartate aminotransferase and alanine aminotransferase, ROS, apoptotic cell death, lipid peroxidation and improved the antioxidants' levels in the ethanol-challenged HepG2 cells. In conclusion, our findings unveiled the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats. It could be a promising agent to treat alcoholic liver disease in the future.
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Affiliation(s)
- Rongsheng Wang
- Department of General Surgery, The Second Affiliated Hospital of Wannan Medical College, Wuhu, China
| | - Jinji Mu
- Department of Gastroenterology, People's Hospital of Tongchuan, Tongchuan, China
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Abstract
The incidence of alcoholic hepatitis is increasing while the mortality rate remains high. The single current available therapy for severe alcoholic hepatitis is administration of corticosteroids for patients with severe alcoholic hepatitis, which has demonstrated limited benefits, providing a short-term mortality benefit with a marginal response rate. There is a need for developing safe and effective therapies. This article reviews novel therapies targeting various mechanisms in the pathogenesis of alcoholic hepatitis, such as the gut-liver axis, inflammatory cascade, oxidative stress, and hepatic regeneration. Current ongoing clinical trials for alcoholic hepatitis also are described.
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Affiliation(s)
- Ma Ai Thanda Han
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, H-526, Newark, NJ 07103, USA
| | - Nikolaos Pyrsopoulos
- Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, 185 South Orange Avenue, H-536, Newark, NJ 07103, USA.
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Bhatti S, Kim D, Ahmed A, Cholankeril G. Current Trends in Liver Transplantation for Alcoholic Hepatitis. Clin Liver Dis 2021; 25:625-634. [PMID: 34229844 DOI: 10.1016/j.cld.2021.04.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Liver transplantation (LT) for alcohol-related or alcoholic hepatitis (AH) remains a controversial treatment option. However, recent studies have shown promising outcomes for LT in a subgroup of patients with AH. Considering these emerging data, LT as definitive therapy for severe AH refractory to medical management is gaining recognition. However, concerns of alcohol recidivism pose a significant barrier to perform LT for this indication. Predictive models can be utilized to develop a selection criterion to identify suitable candidates for LT. Hence, carefully selected patients with severe AH and low risk of alcohol relapse can be considered for LT.
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Affiliation(s)
- Sundus Bhatti
- Baylor College of Medicine, Section of Gastroenterology and Hepatology, 6620 Main Street, Suite 1450, Houston, TX 77030, USA; Baylor College of Medicine, Division of Abdominal Transplantation, Houston, TX, USA
| | - Donghee Kim
- Stanford University School of Medicine, Division of Gastroenterology and Hepatology, 750 Welch Road, #210, Stanford, CA 94304, USA
| | - Aijaz Ahmed
- Stanford University School of Medicine, Division of Gastroenterology and Hepatology, 750 Welch Road, #210, Stanford, CA 94304, USA
| | - George Cholankeril
- Baylor College of Medicine, Section of Gastroenterology and Hepatology, 6620 Main Street, Suite 1450, Houston, TX 77030, USA; Baylor College of Medicine, Division of Abdominal Transplantation, Houston, TX, USA.
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Cabré N, Duan Y, Llorente C, Conrad M, Stern P, Yamashita D, Schnabl B. Colesevelam Reduces Ethanol-Induced Liver Steatosis in Humanized Gnotobiotic Mice. Cells 2021; 10:cells10061496. [PMID: 34198609 PMCID: PMC8232222 DOI: 10.3390/cells10061496] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/03/2021] [Accepted: 06/05/2021] [Indexed: 12/12/2022] Open
Abstract
Alcohol-related liver disease is associated with intestinal dysbiosis. Functional changes in the microbiota affect bile acid metabolism and result in elevated serum bile acids in patients with alcohol-related liver disease. The aim of this study was to identify the potential role of the bile acid sequestrant colesevelam in a humanized mouse model of ethanol-induced liver disease. We colonized germ-free (GF) C57BL/6 mice with feces from patients with alcoholic hepatitis and subjected humanized mice to the chronic–binge ethanol feeding model. Ethanol-fed gnotobiotic mice treated with colesevelam showed reduced hepatic levels of triglycerides and cholesterol, but liver injury and inflammation were not decreased as compared with non-treated mice. Colesevelam reduced hepatic cytochrome P450, family 7, subfamily a, polypeptide 1 (Cyp7a1) protein expression, although serum bile acids were not lowered. In conclusion, our findings indicate that colesevelam treatment mitigates ethanol-induced liver steatosis in mice.
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Affiliation(s)
- Noemí Cabré
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (N.C.); (Y.D.); (C.L.)
| | - Yi Duan
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (N.C.); (Y.D.); (C.L.)
| | - Cristina Llorente
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (N.C.); (Y.D.); (C.L.)
| | - Mary Conrad
- Axial Therapeutics, Woburn, MA 01801, USA; (M.C.); (P.S.); (D.Y.)
| | - Patrick Stern
- Axial Therapeutics, Woburn, MA 01801, USA; (M.C.); (P.S.); (D.Y.)
| | - Dennis Yamashita
- Axial Therapeutics, Woburn, MA 01801, USA; (M.C.); (P.S.); (D.Y.)
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA; (N.C.); (Y.D.); (C.L.)
- Department of Medicine, VA San Diego Healthcare System, San Diego, CA 92161, USA
- Correspondence:
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Wu T, Shah V. Biomarkers of endothelial dysfunction in alcoholic hepatitis. Hepatol Int 2021; 15:855-857. [PMID: 34043159 DOI: 10.1007/s12072-021-10202-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 04/29/2021] [Indexed: 10/21/2022]
Affiliation(s)
- Tiffany Wu
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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Chang B, Huang A, Saxena R, Sun Y, Liu S, Zhou G, Li B, Teng G, Zhao J, Zhang W, Jiang Y, Han S, Yang Z, Zhao J, Zou Z, Liangpunsakul S. Hepatic Histopathology Among Excessive Drinkers Without Advanced Liver Disease. Alcohol Alcohol 2021; 56:669-677. [PMID: 33765150 DOI: 10.1093/alcalc/agab017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 02/07/2021] [Accepted: 02/23/2021] [Indexed: 11/13/2022] Open
Abstract
AIMS Alcohol-associated liver disease represents a spectrum of histopathological changes from steatosis to advanced fibrosis and cirrhosis. The major goals of this retrospective study were to characterize the histologic features in patients with excessive alcohol use who presented with an abnormal hepatic panel and/or abnormal radiographic imaging and did not meet the clinical diagnosis of alcoholic hepatitis or cirrhosis. METHODS We performed a retrospective study to describe hepatic histology of 62 and 83 excessive drinkers with normal and abnormal serum aspartate transaminase, respectively. The types of inflammatory cells in the liver were characterized by immunohistochemistry for CD4, CD8, CD20, CD68 and myeloperoxidase. RESULTS Among 62 patients with aspartate aminotransferase (AST) ≤ 50 U/L, 37% had histological evidence of steatosis. Of these, we found evidence of hepatocyte ballooning (21%), lobular inflammation (50%), portal inflammation (52%) and fibrosis (14%). For those with AST > 50 U/L, the presence of hepatic steatosis, lobular inflammation and portal inflammation was observed in 29, 60 and 69% of patients, respectively. Fibrosis was found in 33%, four with bridging fibrosis, and one with cirrhosis. We observed the aggregation of CD68+ macrophages, rather than normally distributed with minimal neutrophilic infiltration. Lobular and portal lymphocytic infiltrations are primarily CD8+ T cells. CONCLUSION Abnormal hepatic histopathology occurs in excessive drinkers with normal transaminase activity. Future studies to determine the diagnostic modalities to detect such abnormalities and to better understand its clinical implications and long-term outcome are needed.
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Affiliation(s)
- Binxia Chang
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Ang Huang
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Romil Saxena
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Yin Sun
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Shuhong Liu
- Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Guangde Zhou
- Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Baosen Li
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Guangju Teng
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Jun Zhao
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Wei Zhang
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
| | - Jingmin Zhao
- Department of Pathology, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Zhengsheng Zou
- The Center for Non-Infectious Liver Disease, Institute of Alcoholic liver Disease, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, 100039, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, 46202, USA
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Translational Approaches with Antioxidant Phytochemicals against Alcohol-Mediated Oxidative Stress, Gut Dysbiosis, Intestinal Barrier Dysfunction, and Fatty Liver Disease. Antioxidants (Basel) 2021; 10:antiox10030384. [PMID: 33806556 PMCID: PMC8000766 DOI: 10.3390/antiox10030384] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 02/25/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
Emerging data demonstrate the important roles of altered gut microbiomes (dysbiosis) in many disease states in the peripheral tissues and the central nervous system. Gut dysbiosis with decreased ratios of Bacteroidetes/Firmicutes and other changes are reported to be caused by many disease states and various environmental factors, such as ethanol (e.g., alcohol drinking), Western-style high-fat diets, high fructose, etc. It is also caused by genetic factors, including genetic polymorphisms and epigenetic changes in different individuals. Gut dysbiosis, impaired intestinal barrier function, and elevated serum endotoxin levels can be observed in human patients and/or experimental rodent models exposed to these factors or with certain disease states. However, gut dysbiosis and leaky gut can be normalized through lifestyle alterations such as increased consumption of healthy diets with various fruits and vegetables containing many different kinds of antioxidant phytochemicals. In this review, we describe the mechanisms of gut dysbiosis, leaky gut, endotoxemia, and fatty liver disease with a specific focus on the alcohol-associated pathways. We also mention translational approaches by discussing the benefits of many antioxidant phytochemicals and/or their metabolites against alcohol-mediated oxidative stress, gut dysbiosis, intestinal barrier dysfunction, and fatty liver disease.
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Kedarisetty CK, Kumar A, Sarin SK. Insights into the Role of Granulocyte Colony-Stimulating Factor in Severe Alcoholic Hepatitis. Semin Liver Dis 2021; 41:67-78. [PMID: 33764486 DOI: 10.1055/s-0040-1719177] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Alcohol use disorder is the predominant cause of chronic liver disease globally. The standard of care for the treatment of alcoholic hepatitis, corticosteroids, has been shown to provide a therapeutic response in ∼60% of carefully selected patients with a short-term survival benefit. The patients who do not respond to steroids, or are ineligible due to infections or very severe disease, have little options other than liver transplantation. There is, thus, a large unmet need for new therapeutic strategies for this large and sick group of patients. Granulocyte colony stimulating factor (G-CSF) has been shown to favorably modulate the intrahepatic immune milieu and stimulate the regenerative potential of the liver. Initial studies have shown encouraging results with G-CSF in patients with severe alcoholic hepatitis. It has also been found to help steroid nonresponsive patients. There is, however, a need for careful selection of patients, regular dose monitoring and close observation for adverse events of G-CSF. In this review, we analyze the basis of the potential benefits, clinical studies, cautions and challenges in the use of G-CSF in alcoholic hepatitis.
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Affiliation(s)
- Chandan Kumar Kedarisetty
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.,Department of Hepatology, Sri Ramachandra Institute of Higher Education and Research, Chennai, Tamil Nadu, India
| | - Anupam Kumar
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.,Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
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36
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Baig M, Walayat S, Dhillon S, Puli S. Efficacy of Granulocyte Colony Stimulating Factor in Severe Alcoholic Hepatitis: A Systematic Review and Meta-Analysis. Cureus 2020; 12:e10474. [PMID: 33083176 PMCID: PMC7567328 DOI: 10.7759/cureus.10474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Accepted: 09/15/2020] [Indexed: 11/05/2022] Open
Abstract
Background Severe alcoholic hepatitis is a condition with a very high mortality rate and there is a paucity of evidence regarding efficacy and safety of most available therapeutic options. The present systematic review and meta-analysis aims to assess the survival benefit of granulocyte colony stimulating factor (G-CSF) in patients with severe alcoholic hepatitis. Methods Studies involving adult patients receiving G-CSF for severe alcoholic hepatitis were searched in MEDLINE, Ovid journals, MEDLINE nonindexed citations, and Cochrane Central Register of Controlled Trials and Database of Systematic Reviews. Pooling was conducted by both fixed and random effects model. Results The initial search identified 543 reference articles; of these 24 relevant articles were selected and reviewed. Data was extracted from four studies (n = 136) which met the inclusion criteria. In the pooled analysis, the 90-day survival in the G-CSF group was 80.03% (95% CI = 69.93-88.49) compared to 40.92% (95% CI = 29.76-52.58) in the Standard Medical Therapy (SMT) group. At 28 days, the Model for End-Stage Liver Disease (MELD) score lowered by 4.89 (95% CI = 4.13-5.64) in the G-CSF group compared to 4.00 (95% CI = 3.25-4.75) in the SMT group. Child-Turcotte-Pugh score declined by 2.26 (95% CI = 1.90-2.63) in the G-CSF group after 28 days compared to 0.91 (95% CI = 0.59-1.23) in the SMT group. At 28 days, Maddrey Discriminant Function score lowered by 39.79 (95% CI = 34.22-45.36) in the G-CSF group compared to 12.39 (95% CI = 6.90-17.88) in the SMT group. Conclusions In patients with severe alcoholic hepatitis, G-CSF therapy resulted in significantly improved 90-day survival compared to SMT. It also demonstrated significant reduction in severity indices (Child-Turcotte-Pugh, MELD, and Maddrey discriminant function) after 28 days of treatment. There certainly is a need for further studies, including development of personalized therapeutic dosing schedules, for G-CSF administration.
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Affiliation(s)
- Muhammad Baig
- Gastroenterology, OSF St. Francis Medical Center/University of Illinois College of Medicine at Peoria, Peoria, USA
| | - Saqib Walayat
- Gastroenterology, OSF St. Francis Medical Center/University of Illinois College of Medicine at Peoria, Peoria, USA
| | - Sonu Dhillon
- Gastroenterology, OSF St. Francis Medical Center/University of Illinois College of Medicine at Peoria, Peoria, USA
| | - Srinivas Puli
- Gastroenterology, OSF St. Francis Medical Center/University of Illinois College of Medicine at Peoria, Peoria, USA
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37
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Xiang X, Hwang S, Feng D, Shah VH, Gao B. Interleukin-22 in alcoholic hepatitis and beyond. Hepatol Int 2020; 14:667-676. [PMID: 32892258 PMCID: PMC7572732 DOI: 10.1007/s12072-020-10082-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Accepted: 08/17/2020] [Indexed: 12/12/2022]
Abstract
Alcoholic hepatitis (AH) is a clinical syndrome characterized by jaundice and progressive inflammatory liver injury in patients with a history of prolonged periods of excess alcohol consumption and recent heavy alcohol abuse. Severe AH is a life-threatening form of alcohol-associated liver disease with a high short-term mortality rate around 30-50% at one month from the initial presentation. A large number of pro-inflammatory mediators, metabolic pathways, transcriptional factors and epigenetic factors have been suggested to be associated with the development and progression of AH. Several factors may contribute to liver failure and mortality in patients with severe AH including hepatocyte death, inflammation, and impaired liver regeneration. Although the pathogeneses of AH have been extensively investigated and many therapeutic targets have been identified over the last five decades, no new drugs for AH have been successfully developed. In this review, we discuss interleukin-22 (IL-22) biology and its roles of anti-apoptosis, anti-fibrosis, anti-oxidation, anti-bacterial infection and regenerative stimulation in protecting against liver injury in many preclinical models including several recently developed models such as chronic-plus-binge ethanol feeding, acute-on-chronic liver failure, C-X-C motif chemokine ligand 1 plus high-fat diet-induced nonalcoholic steatohepatitis. Finally, clinical trials of IL-22 for the treatment of AH are also discussed, which showed some promising benefits for AH patients.
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Affiliation(s)
- Xiaogang Xiang
- Department of Infectious Diseases, Translational Laboratory of Liver Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Seonghwan Hwang
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, 55902, USA
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute On Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, 20892, USA.
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Arab JP, Sehrawat TS, Simonetto DA, Verma VK, Feng D, Tang T, Dreyer K, Yan X, Daley WL, Sanyal A, Chalasani N, Radaeva S, Yang L, Vargas H, Ibacache M, Gao B, Gores GJ, Malhi H, Kamath PS, Shah VH. An Open-Label, Dose-Escalation Study to Assess the Safety and Efficacy of IL-22 Agonist F-652 in Patients With Alcohol-associated Hepatitis. Hepatology 2020; 72:441-453. [PMID: 31774566 PMCID: PMC7250715 DOI: 10.1002/hep.31046] [Citation(s) in RCA: 137] [Impact Index Per Article: 27.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Accepted: 11/07/2019] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND AIMS Interleukin-22 has beneficial effects on inflammation and impaired hepatic regeneration that characterize alcohol-associated hepatitis (AH). F-652 is a recombinant fusion protein of human interleukin-22 and immunoglobulin G2 fragment crystallizable. This study aims to assess the safety and efficacy signals of F-652 in patients with moderate and severe AH. APPROACH AND RESULTS A phase-2 dose-escalating study was carried out. F-652 (10 μg/kg, 30 μg/kg, or 45 μg/kg) administered on days 1 and 7 was tested in 3 patients each with moderate (Model for End-Stage Liver Disease [MELD] scores: 11-20) and severe AH (MELD scores: 21-28). Safety was defined by absence of serious adverse events and efficacy was assessed by Lille score, changes in MELD score, and serum bilirubin and aminotransferases at days 28 and 42. Three independent propensity-matched comparator patient cohorts were used. Plasma extracellular vesicles and multiplex serum cytokines were measured to assess inflammation and hepatic regeneration. Eighteen patients (9 moderate and 9 severe AH) were enrolled, 66% were male, and the mean age was 48 years. The half-life of F-652 following the first dose was 61-85 hours. There were no serious adverse events leading to discontinuation. The MELD score and serum aminotransferases decreased significantly at days 28 and 42 from baseline (P < 0.05). Day-7 Lille score was 0.45 or less in 83% patients as compared with 6%, 12%, and 56% among the comparator cohorts. Extracellular vesicle counts decreased significantly at day 28 (P < 0.013). Cytokine inflammatory markers were down-regulated, and regeneration markers were up-regulated at days 28 and 42. CONCLUSIONS F-652 is safe in doses up to 45 μg/kg and associated with a high rate of improvement as determined by Lille and MELD scores, reductions in markers of inflammation and increases in markers of hepatic regeneration. This study supports the need for randomized placebo-controlled trials to test the efficacy of F-652 in AH.
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Affiliation(s)
- Juan P. Arab
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, CHILE
| | - Tejasav S. Sehrawat
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | | | - Vikas K. Verma
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Dechun Feng
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Tom Tang
- Generon Corporation Ltd. Shanghai, China
| | | | | | | | - Arun Sanyal
- Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Naga Chalasani
- Indiana University School of Medicine, Indianapolis, IN, USA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA
| | - Liu Yang
- Division of Gastroenterology and Hepatology, Mayo Clinic, Jacksonville, FL, USA
| | - Hugo Vargas
- Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, USA
| | - Mauricio Ibacache
- División Anestesiología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, CHILE
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD, USA
| | - Gregory J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Harmeet Malhi
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Du B, Tan XH, Cheng L, Wang F, Zhang HF. MiR-451a ameliorates alcoholic hepatitis via repressing HDAC8-mediated proinflammatory response. Kaohsiung J Med Sci 2020; 36:904-910. [PMID: 32643864 DOI: 10.1002/kjm2.12272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Revised: 06/08/2020] [Accepted: 06/19/2020] [Indexed: 12/17/2022] Open
Abstract
Alcoholic hepatitis (AH) is identified as an inflammatory syndrome with high morbidity and mortality as a result of severe hepatocellular dysfunction and liver injury. Accumulated studies indicated that miRNAs are involved in AH. The potential effect of miR-451a in AH mice was examined in the current study. A mice AH model was established and the miR-451a expression in AH mice compared with the sham group was tested by real-time polymerase chain reaction (qRT-PCR). AH mice were injected with pre-miR-451a lentivirus for miR-451a overexpression and histone deacetylase (HDAC8) lentivirus for HDAC8 overexpression in AH mice. The underlying mechanisms were explored by searching the potential target genes of miR-451a in miRanda database and then we confirmed this. We found that miR-451a expression was significantly decreased in AH mice compared with the sham group. Moreover, miR-451a overexpression alleviated alcohol-induced liver inflammation and injuries of AH mice. Additionally, further mechanism exploration disclosed that HDAC8 was a target of miR-451a. The protective effect of miR-451a on AH in AH mice was abolished by HDAC8 overexpression. In summary, miR-451a ameliorates AH via repressing HDAC8-mediated proinflammatory response.
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Affiliation(s)
- Bo Du
- Department of Hepatobiliary Surgery, The People's Hospital of Kaizhou District, Chongqing, China
| | - Xiao-Hong Tan
- Department of Hepatobiliary Surgery, The People's Hospital of Kaizhou District, Chongqing, China
| | - Ling Cheng
- Department of Hepatobiliary Surgery, The People's Hospital of Kaizhou District, Chongqing, China
| | - Feng Wang
- Department of Physiology, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
| | - Hai-Feng Zhang
- Department of Physiology, Inner Mongolia Medical University, Hohhot, Inner Mongolia Autonomous Region, China
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Bertha M, Maddur H. Highlights From the AASLD/EASL ALD Endpoints Conference 2019. Clin Liver Dis (Hoboken) 2020; 15:215-218. [PMID: 32617152 PMCID: PMC7326629 DOI: 10.1002/cld.927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 01/11/2020] [Indexed: 02/04/2023] Open
Abstract
Watch a video presentation of this article Watch an interview with the author.
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Xiong J, Ni J, Chen C, Wang K. miR‑148a‑3p regulates alcoholic liver fibrosis through targeting ERBB3. Int J Mol Med 2020; 46:1003-1012. [PMID: 32582976 PMCID: PMC7387083 DOI: 10.3892/ijmm.2020.4655] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Accepted: 04/14/2020] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease greatly affects human health. Previous studies have identified that microRNAs (miRNAs) are associated with the pathogenesis of alcoholic liver fibrosis (ALF). Therefore, the present study explored the regulatory mechanism of miR-148a-3p in ALF. An ALF model was established in rats by alcohol gavage, followed by treatment with miR-148a-3p. Reverse transcription-quantitative (RT-q) PCR was performed to detect miR-148a-3p expression in the rat liver tissues. The levels of lactate dehydrogenase (LDH), aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase (ALP) were determined by enzyme-labeled colorimetry. Liver damage was evaluated by liver indices and histology. The direct target gene of miR-148a-3p was predicted by a dual luciferase reporter assay. The effects of miR-148a-3p and miR-148a-3p in combination with receptor tyrosine-protein kinase erbB-3 (ERBB3) on HSC-T6 cell viability and apoptosis were detected by MTT and flow cytometry assays, respectively. Western blotting and RT-qPCR assays were performed to detect the expression levels of proteins and mRNA associated with fibrosis and apoptosis. The data showed that miR-148a-3p mimics inhibited the expression levels of AST, ALT, ALP, LDH, α-SMA and type I collagen in the model, decreased the liver indices, and improved the liver damage caused by alcohol. ERBB3, which was predicted as the direct target gene of miR-148a-3p, reversed the effects of ERBB3 on promoting cell viability and inhibiting apoptosis. Concomitantly, miR-148a-3p reversed the increased expression of Bcl-2 and inhibited the expression levels of Bax and c-cleaved-3 caused by ERBB3. These data suggested that miR-148a-3p regulated ALF and the viability and apoptosis of hepatic stellate cells through targeting ERBB3.
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Affiliation(s)
- Jie Xiong
- Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Jianbo Ni
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Congying Chen
- Department of Gastroenterology and Hepatology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, P.R. China
| | - Kezhou Wang
- Department of Pathology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, P.R. China
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Ji X, Li L, Lu P, Li X, Tian D, Liu M. NLRP6 exerts a protective role via NF-kB with involvement of CCL20 in a mouse model of alcoholic hepatitis. Biochem Biophys Res Commun 2020; 528:485-492. [PMID: 32507279 DOI: 10.1016/j.bbrc.2020.05.171] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 05/23/2020] [Indexed: 12/18/2022]
Abstract
Alcoholic hepatitis (AH) is an important form of alcoholic liver disease (ALD), and its incidence is continuously increasing leading to advanced disease burden. The NOD-like receptors (NLRs) are a specialized group of intracellular pattern recognition receptors, which participate in inflammatory diseases. However, the role of NLRs in the pathogenesis of AH still remain obscure. The animal model of alcoholic hepatitis in mice was established according to National Institute on Alcohol Abuse and Alcoholism (NIAAA) method. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the expression of NLR family members in liver tissues of the ethanol-fed(EtOH-fed)group and pair-fed group. NLRP6 was overexpressed in mice by injecting Recombinant Adeno-Associated Virus into the tail vein. Mouse Cytokines and Chemokines RT2 Profiler PCR Array was used to analyze the related cytokines and chemokines involved in the development of alcoholic hepatitis. Among the NLR family members, the expression of NLRP6 decreased most significantly in the animal model of AH. Our results demonstrated that overexpression of NLRP6 in vivo obviously alleviated steatosis, inflammation and fibrosis in liver. Meanwhile, the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels in mice also decreased. Besides, Chemokine (C-C motif) ligand 20(CCL20) was one of the most significantly up-regulated chemokines in the mouse AH model and CCL20 was participated in NLRP6-mediated AH. NLRP6 could inhibit the activation of nuclear factor (NF)-κB signaling pathway in vitro and in vivo. Furthermore, the activation, proliferation, and migration of hepatic stellate cells was enhanced after downregulation of NLRP6. In summary, NLRP6 may play a protective role in the development of AH. NLRP6 could inhibit activation of NF-κB signaling pathway in AH.
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Affiliation(s)
- Xiaoyu Ji
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lili Li
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Panpan Lu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xin Li
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Dean Tian
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Mei Liu
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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Björnsson ES, Hauksson K, Sigurdardottir R, Arnardottir M, Agustsson AS, Lund SH, Kalaitzakis E. Abstinence from alcohol and alcohol rehabilitation therapy in alcoholic liver disease: a population-based study. Scand J Gastroenterol 2020; 55:472-478. [PMID: 32233877 DOI: 10.1080/00365521.2020.1743751] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Objective: Abstinence from alcohol is recommended in patients diagnosed with alcoholic hepatitis (AH) and alcoholic cirrhosis (AC). We aimed to determine the impact of alcohol abstinence on prognosis of patients with AC and AH.Methods: All incident AC and AH patients in Iceland 2001-2016 were identified. Cirrhosis was confirmed clinically, biochemically, with imaging and histologically. Abstinence, alcohol rehabilitation and survival were analyzed.Results: Overall, 169 patients with AC and/or AH were identified. Eleven died during index hospitalization, leaving 158 patients for final analysis, median (IQR) age 56 years (48-65), 72% males. Over all 61 patients (39%) had AC, 40 (25%) AH and 57 (36%) features of both. Thirty-nine percent of patients remained abstinent during follow-up and 63% underwent alcohol rehabilitation. Moderate to severe ascites at diagnosis (odds ratio (OR): 3.05, 95% confidence interval (CI): 1.37-7.02) and lack of alcoholic rehabilitation (OR: 5.28, 95% CI: 2.24- 14.11) were independent predictors of abstinence. Abstinence at one year of follow-up was not related to increased survival. Patients surviving one year, abstinence during follow-up was related to increased survival for both groups.Conclusion: Abstinence from alcohol following AC/AH diagnosis was achieved in 39% of patients. Abstinence was not related to increased survival for alcoholic liver disease patients at one-year, which might partly indicate that this might be a marker that some patients were 'too sick to drink'. AC and AH patients who survived one year and remained abstinent had a favorable long-term prognosis.
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Affiliation(s)
- Einar S Björnsson
- Faculty of Medicine, University of Iceland, Reykjavík, Iceland.,Department of Gastroenterology, Landspitali University Hospital, Reykjavik, Iceland
| | - Kristjan Hauksson
- Department of Gastroenterology, Landspitali University Hospital, Reykjavik, Iceland
| | | | - Margret Arnardottir
- Department of Gastroenterology, Landspitali University Hospital, Reykjavik, Iceland
| | - Arnar S Agustsson
- Department of Gastroenterology, Landspitali University Hospital, Reykjavik, Iceland
| | - Sigrun H Lund
- Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Evangelos Kalaitzakis
- Digestive Disease Center, Copenhagen University Hospital/Herlev, University of Copenhagen, Copenhagen, Denmark.,Department of Gastroenterology, University Hospital of Heraklion, University of Crete, Heraklion, Greece
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Adejumo AC, Cholankeril G, Iqbal U, Yoo ER, Boursiquot BC, Concepcion WC, Kim D, Ahmed A. Readmission Rates and Associated Outcomes for Alcoholic Hepatitis: A Nationwide Cohort Study. Dig Dis Sci 2020; 65:990-1002. [PMID: 31372912 DOI: 10.1007/s10620-019-05759-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2019] [Accepted: 07/23/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Alcoholic hepatitis (AH) can lead to sudden and severe hepatic decompensation necessitating recurrent hospitalizations. We evaluated the trends, predictors, and healthcare cost burden of AH-related readmissions in the USA. METHODS Utilizing the National Readmissions Database 2010-2014, we performed a retrospective longitudinal analysis to identify the index readmission with AH for up to 90 days after discharge. Annual trends of 30- and 90-day AH-related readmissions were calculated. Predictors of 30- and 90-day readmission were determined by multivariate logistic regression. Annual healthcare cost burden associated with AH-linked readmissions was estimated. RESULTS Of the 21,572 (unweighted: 50,769) AH-related hospitalizations, 4917 (22.8%) and 7890 (36.6%) were readmitted in 30 and 90 day, respectively, with rates that were statistically unchanged from 2010 to 2014. Predictors of 30-day readmissions included female gender, hepatitis C virus infection, cirrhosis, ascites, acute kidney injury, urinary tract infection, history of bariatric surgery, chronic pancreatitis, and high medical comorbidity index. Acute pancreatitis and palliative care consultation were associated with a lower risk of 30-day readmission. Predictors of 90-day readmission were similar to risk factors for 30-day readmission. From 2010 to 2014, the annual cost (and total hospitalization days) burden increased in 2014 to $164 million (22,244 days) and $321 million (42,772 days) for 30- and 90-day AH-related readmissions, respectively. CONCLUSION Despite relatively stable trends in AH-related readmission, the total LOS and cost has been rising. A target-directed approach with a focus on high-risk subpopulations may help understand the unique challenges associated with the rising cost of AH-related readmissions.
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Affiliation(s)
- Adeyinka C Adejumo
- Department of Medicine, North Shore Medical Center, 81 Highland Ave., Salem, MA, 01970, USA.
- Department of Medicine, Tufts University School of Medicine, Boston, MA, USA.
| | - George Cholankeril
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Umair Iqbal
- Department of Medicine, Geisinger Medical Center, Danville, PA, USA
| | - Eric R Yoo
- Department of Internal Medicine, Santa Clara Valley Medical Center, San Jose, CA, USA
| | - Brian C Boursiquot
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Waldo C Concepcion
- Department of Surgery, Abdominal Transplantation, Stanford University School of Medicine, Stanford, CA, USA
| | - Donghee Kim
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
| | - Aijaz Ahmed
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA, USA
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Abstract
Alcoholic hepatitis is the severest clinical presentation of alcoholic liver disease. Lacking an effective pharmacologic treatment, alcoholic hepatitis is associated with a poor prognosis and its recovery relies mostly on abstinence. With alcohol use disorder being universally on the rise, the impact of alcoholic hepatitis on society and health-care costs is expected to increase significantly. Prognostic factors and liver biopsy can help with timely diagnosis, to determine eligibility and response to corticosteroids, and for prognostication and transplant referral. Although recent discoveries in the pathophysiology of alcoholic hepatitis are encouraging and could pave the way for novel treatment modalities, a multidisciplinary approach considering timely identification and treatment of liver-related complications, infectious and metabolic disease, malnutrition, and addiction counseling should be emphasized. Apart from proper selection of candidates, transplant programs should provide adequate post-transplant addiction support in order to make of early liver transplantation for alcoholic hepatitis the ultimate sobering experience in the next decade.
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Affiliation(s)
- Vikrant Rachakonda
- Division of Gastroenterology and Hepatology, Starzl Transplantation Institute, and Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Ramon Bataller
- Division of Gastroenterology and Hepatology, Starzl Transplantation Institute, and Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
| | - Andres Duarte-Rojo
- Division of Gastroenterology and Hepatology, Starzl Transplantation Institute, and Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA
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Crabb DW, Im GY, Szabo G, Mellinger JL, Lucey MR. Diagnosis and Treatment of Alcohol-Associated Liver Diseases: 2019 Practice Guidance From the American Association for the Study of Liver Diseases. Hepatology 2020; 71:306-333. [PMID: 31314133 DOI: 10.1002/hep.30866] [Citation(s) in RCA: 546] [Impact Index Per Article: 109.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Accepted: 05/31/2019] [Indexed: 12/12/2022]
Affiliation(s)
- David W Crabb
- Indiana University School of Medicine, Indianapolis, IN
| | - Gene Y Im
- Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gyongyi Szabo
- University of Massachusetts Medical School, Worcester, MA
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Identification of key genes, MicroRNAs and potentially regulated pathways in alcoholic hepatitis by integrative analysis. Gene 2019; 720:144035. [DOI: 10.1016/j.gene.2019.144035] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2019] [Revised: 07/29/2019] [Accepted: 07/31/2019] [Indexed: 12/25/2022]
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Singal AK, Kamath PS. Acute on chronic liver failure in non-alcoholic fatty liver and alcohol associated liver disease. Transl Gastroenterol Hepatol 2019; 4:74. [PMID: 31728431 DOI: 10.21037/tgh.2019.09.11] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 09/18/2019] [Indexed: 12/12/2022] Open
Abstract
Acute on chronic liver failure (ACLF) presents acutely with multiple organ failure and is precipitated by an acute event. The syndrome has high short-term mortality with a potential of returning to baseline liver function if the precipitating event is controlled and patient/s survive the acute event. With heterogeneous definition across the globe of this syndrome, there is a clinical unmet need to homogenize this definition as basis for developing pathogenesis targets, collaboration across countries and centers, and identifying new therapeutic targets. Although, the syndrome can occur in any chronic liver disease with or without cirrhosis, the increasing prevalence of nonalcoholic fatty liver disease (NAFLD) and alcohol associated liver disease (AALD) all across the world, this review will discuss specific issues regarding ACLF among patients with chronic liver disease from NAFLD and ALD.
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Affiliation(s)
- Ashwani K Singal
- Division of Transplant Hepatology, Avera Transplant Institute, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Medical School, Rochester, MN, USA
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Wong VWS, Singal AK. Emerging medical therapies for non-alcoholic fatty liver disease and for alcoholic hepatitis. Transl Gastroenterol Hepatol 2019; 4:53. [PMID: 31463412 PMCID: PMC6691078 DOI: 10.21037/tgh.2019.06.06] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2019] [Accepted: 05/29/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are currently the two most common liver diseases in the world. Alcoholic hepatitis (AH), a unique clinical syndrome among ALD patients has high short-term mortality. Apart from controlling the risk factor for individual respective disease, there are no Food and Drug Administration (FDA) approved medical therapies for these diseases. Over the last 5-10 years, the field has extensively grown with many new targets being studied in randomized clinical trials for these diseases, with many of these drugs being tested in both the conditions. In this chapter, we will describe the novel therapeutic agents and current status of ongoing clinical trials with these agents for the treatment of NAFLD and/or AH.
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Affiliation(s)
- Vincent Wai-Sun Wong
- Department of Medicine and Therapeutics, the Chinese University of Hong Kong, Hong Kong, China
- State Key Laboratory of Digestive Disease, the Chinese University of Hong Kong, Hong Kong, China
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, Avera Transplant Institute, University of South Dakota Sanford School of Medicine, Sioux Falls, SD, USA
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Noronha L, FitzGerald E, Pierce JR. Outcomes of Patients Hospitalized for Severe Acute Alcoholic Hepatitis. South Med J 2019; 112:363-368. [PMID: 31282964 DOI: 10.14423/smj.0000000000000999] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVES Severe acute alcoholic hepatitis is a serious condition in individuals who consume significant quantities of alcohol. We aimed to identify risk factors for short-term mortality with this illness. METHODS Patients with severe acute alcoholic hepatitis admitted to our academic medical center from 2010 to 2012 were identified. Demographic features, laboratory values, and patient outcomes were recorded. In-hospital mortality and transfer to inpatient hospice were combined to calculate overall inpatient mortality. RESULTS A total of 251 hospitalizations of 191 patients were identified. The average age was 43.1 years (standard deviation 9.55). Most patients were men (80.6%). Compared with all adult patients admitted to internal medicine services during the same period, patients self-reporting Native American and Hispanic race/ethnicity were overrepresented (11.1% vs 34.0% and 14.8% vs 27.7%, χ2 P < 0.0001). In-hospital mortality was 20.3%. Another 10% of patients were transferred to inpatient hospice facilities. In the multivariate analysis, higher overall inpatient mortality was associated with an admission bilirubin >20 mg/dL (odds ratio 4.59). Of the patients, 11.9% were readmitted with a complication within 30 days-most commonly septic shock. Of the readmitted patients, the overall inpatient mortality was 86.2%. CONCLUSIONS This study confirms the severity of illness among patients with severe acute alcoholic hepatitis. Patients with the highest total bilirubin levels on admission had the highest overall inpatient mortality. Readmission was a strong predictor of overall in-hospital mortality.
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Affiliation(s)
- Leonard Noronha
- From the Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque
| | - Erin FitzGerald
- From the Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque
| | - J Rush Pierce
- From the Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque
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