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Feng ZG, Geng ZJ, Song Q, Hu H, Tan XY, Zeng SY, Zhou RY, Ma X, Liu Y, Zhang Y. Metabolomics based analysis reveals the therapeutic effects of Incarvillea arguta (Royle) Royle aqueous extract against alcohol-induced liver injury. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 140:156639. [PMID: 40085992 DOI: 10.1016/j.phymed.2025.156639] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 03/08/2025] [Accepted: 03/11/2025] [Indexed: 03/16/2025]
Abstract
BACKGROUND Alcohol-induced liver injury (ALI) poses a significant threat to global human health. The Chinese Yi medicine Liangtoumao (LTM), which originated from the whole plant of Incarvillea arguta Royle (Royle), has been widely used by the Yi ethnic group to prevent and treat ALI and other liver diseases. However, its effectiveness and mechanisms are still under-researched. PURPOSE The objective of our research is to investigate the chemical composition of LTM aqueous extract, evaluate its potential therapeutic intervention effect on ALI, and explore its mechanisms in rat models. METHODS The chemical components and constituents of LTM aqueous extract migrating to the blood were analyzed by UPLC-Q-TOF/MS. Sprague-Dawley rats subjected to chronic binge alcohol exposure were utilized to establish chronic ALI models and evaluate the therapeutic effects of LTM aqueous extract. Serum and spatial metabolomics analyses were used to investigate potential mechanisms. RESULTS A total of 60 chemical components in LTM aqueous extract were identified, with 67 absorbed into the blood, including 29 original compounds and 38 metabolites. Treatment with LTM aqueous extract remarkably alleviated hepatic lesions in livers of ALI rats, improved liver function, reduced oxidative stress and inflammation. Serum metabolomics and hepatic spatial metabolomics identified 30 and 215 differential metabolites, respectively. Metabolic pathways of glyoxylate and dicarboxylate, glycerophospholipid, linoleic acid, taurine and hypotaurine, and cysteine and methionine were closely related to the hepaprotective effects of LTM. CONCLUSION Our research confirmed significant effects of LTM on ALI prevention and treatment for the first time. Metabolomic findings revealed that LTM significantly influences various aspects of lipid metabolism. This study supports expanded mechanism investigations of LTM and explores its possibility as a potential ALI therapy.
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Affiliation(s)
- Zi-Ge Feng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China; College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Zang-Jia Geng
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Qin Song
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Hu Hu
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Xiao-Yan Tan
- Chongqing Three Gorges Medical College, Chongqing 404120, China
| | - Shang-Yu Zeng
- Urban Vocational College of Sichuan, Chengdu 610110, China
| | - Rong-Yu Zhou
- College of Pharmacy and Food, Southwest Minzu University, Chengdu 610225, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yue Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yi Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Ethnic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
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Xu H, Wu Z, Qin J, Li X, Xu F, Wang W, Zhang H, Yin H, Zhu S, Zhang W, Yang Y, Wei Y, Gao L, Liu J, Gao Y, Zheng MH, Zhou H, Qi T, Chen J, Gao Y, Zuo L, Chen J, Liangpunsakul S, Li J, Wang H. Stressed hepatocyte sustains alcohol-associated hepatitis progression by producing leukocyte cell-derived chemotaxin 2. Gut 2025:gutjnl-2024-334318. [PMID: 40139745 DOI: 10.1136/gutjnl-2024-334318] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 03/05/2025] [Indexed: 03/29/2025]
Abstract
BACKGROUND Neutrophil infiltration and hepatocyte damage are indispensable hallmarks in alcohol-associated hepatitis (AH), yet the underlying crosstalk between neutrophils and hepatocytes and its role in AH pathogenesis remain unclear. OBJECTIVE We investigate the regulatory role of leucocyte cell-derived chemotaxin 2 (LECT2) in hepatocyte-neutrophil interaction and its impact on AH progression. DESIGN We used bulk and single-cell RNA sequencing to identify hepatocyte-secreted factors targeting neutrophils. We analysed serum and liver samples from AH patients and employed genetically modified mice alongside in vitro studies. RESULTS RNA-sequencing analysis identified several neutrophil chemokines that are elevated in hepatocytes from AH patients, including LECT2 whose role in AH remains largely unknown. AH patients exhibited increased levels of LECT2 in hepatocytes, positively correlating with the severity of AH. Ethanol-fed mice also exhibited elevated liver LECT2, which was abolished by inhibiting endoplasmic reticulum stress. Functional studies revealed that ethanol-induced liver injury was ameliorated in Lect2-deficient mice but was exacerbated in mice with hepatic overexpression of Lect2. Furthermore, LECT2 exacerbated ethanol-induced liver injury by promoting reactive oxygen species (ROS) through its interaction with prohibitin 2 (PHB2), a neutrophil membrane protein. By directly binding to PHB2, LECT2 disrupts the stable structure of PHB1/PHB2 heterodimerisation, consequently leading to PHB2 degradation, ROS accumulation, neutrophil activation and neutrophil extracellular trap formation. Moreover, therapeutic intervention of LECT2 via Lect2 shRNA ameliorated ethanol-induced liver injury. CONCLUSION Our studies identified a novel vicious cycle between neutrophils and hepatocytes through the LECT2-PHB2 interaction, presenting a promising therapeutic intervention by targeting LECT2 to mitigate AH in patients.
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Affiliation(s)
- Honghai Xu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Department of Pathology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China
| | - Zihao Wu
- Department of Geriatrics, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei, Anhui, China
- Anhui Key Laboratory of Geriatric Immunology and Nutrition Therapy, Hefei, Anhui, China
| | - Jiangfeng Qin
- Department of Infectious Diseases, the People's Hospital of Xuancheng City, Xuancheng, Anhui, China
| | - Xutong Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Feng Xu
- Department of Intensive Care Unit & Central Laboratory, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
| | - Wei Wang
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hui Zhang
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
| | - HeHe Yin
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
| | - Shiwei Zhu
- Department of Pathology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China
| | - Yuanru Yang
- Department of Blood Transfusion, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, Beijing, China
| | - Yuanyuan Wei
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Long Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jiatao Liu
- Department of Pharmacy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yufeng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
- Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, Zhejiang, China
| | - Haoxiong Zhou
- Department of Gastroenterology, Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, Guangdong, China
| | - Tingting Qi
- Hepatology Unit, Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, Guangdong, China
| | - Jinjun Chen
- State Key Laboratory of Organ Failure Research; Key Laboratory of Infectious Diseases Research in South China, Ministry of Education; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Hepatology, Guangdong Provincial Research Center for Liver Fibrosis Engineering and Technology, Guangzhou, Guangdong, China
- Hepatology Unit, Department of Infectious Diseases, Zengcheng Branch, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yanhang Gao
- Department of Hepatology, The First Hospital of Jilin University, Changchun, Jilin, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, Anhui, China
- Laboratory of Molecular Biology, and Department of Biochemistry, Anhui Medical University, Hefei, Anhui, China
| | - Jiong Chen
- State Key Laboratory for Quality and Safety of Agro-Products, School of Marine Sciences, Ningbo University, Ningbo, Zhejiang, China
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jiabin Li
- Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Anhui Center for Surveillance of Bacterial Resistance, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, Anhui, China
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Huda N, Kusumanchi P, Jiang Y, Gao H, Thoudam T, Zeng G, Skill NJ, Sun Z, Liangpunsakul S, Ma J, Yang Z. Silencing FAF2 mitigates alcohol-induced hepatic steatosis by modulating lipolysis and PCSK9 pathway. Hepatol Commun 2025; 9:e0641. [PMID: 39969435 PMCID: PMC11841855 DOI: 10.1097/hc9.0000000000000641] [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: 07/31/2024] [Accepted: 12/02/2024] [Indexed: 02/20/2025] Open
Abstract
BACKGROUND Chronic alcohol consumption leads to lipid accumulation, oxidative stress, cellular damage, and inflammation in the liver, collectively referred to as alcohol-associated liver disease (ALD). FAF2/UBXD8/ETEA (Fas-associated factor 2) is a ubiquitin ligase adaptor protein that plays a crucial role in the ubiquitin-mediated degradation of misfolded proteins in the endoplasmic reticulum. A recent genome-wide association study indicated an association between FAF2 and ALD; however, the exact contribution of FAF2 to ALD pathogenesis remains unclear. METHODS FAF2 was knocked down using AAV-delivered shRNA in C57/BL6 mice. Mice were subjected to a chronic-plus-single binge ethanol feeding (NIAAA) model. Nine hours after gavage, liver, blood, and other organs of interest were collected for gene expression and biochemical analyses. RESULTS We first observed a significant elevation in hepatic FAF2 protein expression in individuals with ALD and in mice subjected to an ethanol-binge model. Interestingly, knocking down FAF2 in the liver using adeno-associated virus serotype 8-delivered short hairpin RNA conferred a protective effect against alcohol-induced liver steatosis in ethanol-binged mice. Transcriptomic analysis revealed that differentially expressed genes were enriched in multiple lipid metabolism regulation pathways. Further analysis of transcription factors regulating these differentially expressed genes suggested potential regulation by SREBP1. Several SREBP1 target genes, including Fasn, Scd1, Lpin1, and Pcsk9 (proprotein convertase subtilisin/kexin type 9), were dysregulated in the livers of ethanol-fed FAF2 knockdown mice. Additionally, Pcsk9 could be regulated through the FOXO3-SIRT6 pathway in the livers of ethanol-fed FAF2 knockdown mice, leading to increased liver low-density lipoprotein receptor expression and reduced plasma LDL cholesterol levels. Furthermore, FAF2 knockdown in mouse liver enhanced adipose triglyceride lipase lipolytic activity by upregulating the adipose triglyceride lipase activator, comparative gene identification-58, and downregulating the adipose triglyceridelipase transport inhibitor, Elmod2, contributing to the alleviation of liver steatosis. CONCLUSIONS Our study uncovers a novel mechanism involving FAF2 in the pathogenesis of ALD.
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Affiliation(s)
- Nazmul Huda
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Praveen Kusumanchi
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yanchao Jiang
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hui Gao
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Themis Thoudam
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Ge Zeng
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Nicholas J. Skill
- Department of Surgery, Louisiana State University Health Science Center, New Orleans, Louisiana, USA
| | - Zhaoli Sun
- Department of Surgery, John Hopkins University, Baltimore, Maryland, USA
| | - Suthat Liangpunsakul
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Research, Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Jing Ma
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Zhihong Yang
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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Danpanichkul P, Suparan K, Chaiyakunapruk N, Auttapracha T, Kongarin S, Wattanachayakul P, Ramadoss V, Suenghataiphorn T, Sukphutanan B, Pang Y, Lui RN, Yang JD, Noureddin M, Díaz LA, Liangpunsakul S, Arab JP, Wijarnpreecha K. Alcohol-related liver and extrahepatic malignancies: burden of disease and socioeconomic disparities in 2019. Eur J Gastroenterol Hepatol 2025; 37:198-206. [PMID: 39589794 DOI: 10.1097/meg.0000000000002882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2024]
Abstract
BACKGROUND Alcohol is linked to various cancers. While many studies have focused on developed countries, the burden of alcohol-related cancers in developing countries remains underexplored. METHODS We analyzed data from the Global Burden of Disease Study (2000-2019) to assess mortality and disability-adjusted life years (DALYs) from alcohol-related cancers in low and low-to-middle sociodemographic index (SDI) countries. RESULTS In 2019, there were 494 730 mortality from alcohol-related cancer. Low and low-middle SDI countries contributed over 15% of global mortality of alcohol-related cancer. Among multiple types of cancer, other pharyngeal cancers in these countries accounted for over 30% of global mortality of alcohol-related cancer. Primary liver cancer exhibited the highest mortality ( n = 16 090) in low and low-middle SDI countries. While deaths and DALYs rates from alcohol-related cancers decreased globally between 2000 and 2019, the related burden increased in low and low-middle SDI countries with a rise in all types of alcohol-related cancers, except for primary liver cancer. The most rapidly growing mortality rates in low SDI were from other pharyngeal cancers (+2.25%), whereas in low-middle SDI countries, colorectal cancer evidenced the highest increase (+2.76%). CONCLUSION The burden from alcohol-related cancer has risen in countries with low and low-to-middle SDI, especially other pharyngeal cancers and colorectal cancer. Policymakers should focus on improving alcohol-related policies as well as screening availability to tackle the associated burden of cancer in resource-constrained countries. However, the difficulty in isolating the impact of alcohol due to limited data on other confounders necessitates caution in interpreting these findings.
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Affiliation(s)
- Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Kanokphong Suparan
- Immunology Unit, Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Nathorn Chaiyakunapruk
- Department of Pharmacotherapy, College of Pharmacy, University of Utah
- IDEAS Center, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA
| | | | | | | | - Vijay Ramadoss
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore, Singapore
| | | | | | - Yanfang Pang
- Affiliated Hospital of Youjiang Medical University for Nationalities
- National Immunological Laboratory of Traditional Chinese Medicine
- Center for Medical Laboratory Science, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Rashid N Lui
- Department of Clinical Oncology, and Division of Gastroenterology and Hepatology, Department of Medicine and Therapeutics, Institute of Digestive Diseases, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Mazen Noureddin
- Houston Research Institute and Houston Methodist Hospital, Houston, Texas, USA
| | - Luis Antonio Díaz
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile
- Observatorio Multicéntrico de Enfermedades Gastrointestinales, OMEGA, Santiago, Chile
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Juan Pablo Arab
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile
- Observatorio Multicéntrico de Enfermedades Gastrointestinales, OMEGA, Santiago, Chile
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine
- Department of Internal Medicine, Banner University Medical Center
- BIO5 Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
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Skladaný Ľ, Žilinčanová D, Kubánek N, Selčanová SA, Havaj D, Laffers L, Žilinčan M, Islam AH, Arab JP, Koller T. Prospective study on time-to-tertiary care in alcohol-associated hepatitis: space-time coordinates as prognostic tool and therapeutic target. Alcohol Alcohol 2025; 60:agae092. [PMID: 39829300 PMCID: PMC11744045 DOI: 10.1093/alcalc/agae092] [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] [Received: 09/06/2024] [Revised: 12/09/2024] [Accepted: 01/02/2025] [Indexed: 01/22/2025] Open
Abstract
BACKGROUND AND AIMS Alcohol-associated hepatitis (AH) frequently triggers acute decompensation (AD) in cirrhosis, with severe AH linked to high short-term mortality, especially in acute-on-chronic liver failure. Current corticosteroid treatments have limited efficacy, highlighting the need for new therapies. We hypothesized that severe AH outcomes are influenced by early specialized care; thus, we examined the impact of time-to-tertiary care (TTTc). METHODS Adults with cirrhosis or advanced chronic liver disease were enrolled (RH7, NCT04767945). AH was diagnosed using National Institute on Alcohol Abuse and Alcoholism criteria. Primary admission site, TTTc, and adverse outcomes (death or liver transplantation) were analyzed. Patients admitted directly to tertiary care were assigned a TTTc of zero. RESULTS Of 221 AD-AH patients, 107 were transferred from secondary care to tertiary care (TTTc >0) and 114 were admitted directly (TTTc = 0). TTTc >0 patients were younger (48.3 vs. 52 years, P = .008) and had more severe disease, as shown by model for end-stage liver disease scores (25.5 vs. 20.8, P < .001) and Maddrey's discriminant function (59.3 vs. 40.6, P < .001). Propensity-score matching yielded 49 case pairs. The Cox model showed that transfer from secondary care was not associated with increased risk, but delayed transfer (days, hazard ratio = 1.03, 95% confidence interval 1.01-1.05) independently predicted adverse outcomes. CONCLUSIONS Delayed initiation of specialized care adversely impacts outcomes in AD-AH. If validated, timely care bundles could improve AH survival, similar to sepsis or vascular syndromes. HIGHLIGHTS AD-AH is a common syndrome associated with high short-term mortality. There is an unmet need for new prognosis-modifying therapies for AH. Currently, in real-life hepatology, refining the existing bundle of care is the only practical option to improve the prognosis of AD-AH. Past experience with acute coronary syndromes, stroke, and sepsis, emphasizing symptoms-to-intervention duration, combined with the recent COVID-19 lockdown finding of increased mortality due to skewed access to specialized liver care indicates that focusing on timely specialized care might be key to improved outcome in certain liver conditions. In this line, we set out to track the number of days elapsing between admission to SC and referral to TC, coining this interval as "time-to-tertiary care" (TTTc). We examined TTTc as a potential compound surrogate that might influence the prognosis in AD-AH. After correcting for important baseline differences, we conclude that the delay of transfer to the tertiary care hospital was independently associated with a worse prognosis with each additional day in TTTc increasing adverse outcomes by nearly 3%.
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Affiliation(s)
- Ľubomír Skladaný
- Department of Hepatology, Gastroenterology, and Transplantation (HEGITO), 2nd Department of Internal Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Námestie L. Svobodu 1, 974 01 Banská Bystrica, Slovakia
| | - Daniela Žilinčanová
- Department of Hepatology, Gastroenterology, and Transplantation (HEGITO), 2nd Department of Internal Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Námestie L. Svobodu 1, 974 01 Banská Bystrica, Slovakia
| | - Natália Kubánek
- Department of Hepatology, Gastroenterology, and Transplantation (HEGITO), 2nd Department of Internal Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Námestie L. Svobodu 1, 974 01 Banská Bystrica, Slovakia
| | - Svetlana Adamcová Selčanová
- Department of Hepatology, Gastroenterology, and Transplantation (HEGITO), 2nd Department of Internal Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Námestie L. Svobodu 1, 974 01 Banská Bystrica, Slovakia
| | - Daniel Havaj
- Department of Hepatology, Gastroenterology, and Transplantation (HEGITO), 2nd Department of Internal Medicine, Slovak Medical University Faculty of Medicine, F. D. Roosevelt Hospital, Námestie L. Svobodu 1, 974 01 Banská Bystrica, Slovakia
| | - Lukáš Laffers
- Department of Mathematics, Faculty of Natural Sciences, Matej Bel University, Tajovského 40, 974 09, Banská Bystrica, Slovakia
| | - Michal Žilinčan
- Department of Radiology, F.D. Roosevelt Hospital, Námestie L. Svobodu 1, 974 01, Banská Bystrica, Slovakia
| | - Alvi H Islam
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Rm. B0-692F, St. Joseph's Health Care, Ontario, Canada
| | - Juan Pablo Arab
- Division of Gastroenterology, Department of Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Rm. B0-692F, St. Joseph's Health Care, Ontario, Canada
- Department of Epidemiology and Biostatistics, Schulich School of Medicine, Western University, London, 1465 Richmond Street, Ontario, Canada
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Libertador Bernando O'Higgins Avenue 340, Santiago, Chile
| | - Tomáš Koller
- Subdivision of Gastroenterology and Hepatology, 5th Department of Internal Medicine, Comenius University Faculty of Medicine, University Hospital Bratislava, Ružinovská 6, 826 06, Bratislava, Slovakia
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Heringer DL, Costa GPA, Weleff J, Rodrigues V, Sengupta S, Anand A. Racial and ethnic disparities in alcohol-associated liver disease hospitalizations in Brazil before and after the COVID-19 pandemic. Ann Hepatol 2024; 30:101742. [PMID: 39653118 DOI: 10.1016/j.aohep.2024.101742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 07/30/2024] [Accepted: 08/22/2024] [Indexed: 12/16/2024]
Abstract
INTRODUCTION AND OBJECTIVES The COVID-19 pandemic has resulted in a greater incidence of alcohol-associated liver disease (ALD) and simultaneously magnified health-related inequalities. We evaluated the impact of race and ethnicity on ALD-related hospitalizations in Brazil. MATERIALS AND METHODS An interrupted time series analysis was used to estimate ALD-related hospitalization in public hospitals in Brazil. Monthly hospitalization rates for 34 consecutive months before and after the point of interruption (March 2020) were calculated using the Sistema de Informações Hospitalares database across four ethnic groups: Black, Pardo, Black, and Pardo combined, and Others (White and Unknown Ethnicity). RESULTS A total of 84,787 ALD-related hospitalizations were recorded during the study period. The mean age of hospitalized patients was 53 years (SD=12.5); 83.6% were male. Immediately after the start of the pandemic, there was a statistically significant decrease in monthly ALD-related hospitalization rates for the whole population and for all ethnic groups. Subsequently, compared to pre-pandemic rates, there was a statistically significant trend increase in the referred hospitalization rates for the total population (0.065, 95% CI= 0.045 to 0.085, p<0.01), black population (0.0028, 95% CI= 0.006 to 0.050, p<0.05), pardo population (0.077, 95% CI= 0.063 to 0.090, p<0.01), and for black and pardo combined population (0.066, 95% CI= 0.053 to 0.079, p<0.01); however, the increase in hospitalization rates among the Others population (0.059, 95% CI= -0,014 to 0.133, p>0.1) was not statistically significant. CONCLUSIONS The pandemic impacted ALD-related monthly hospitalization rates and disproportionately impacted Black and Pardo populations in Brazil.
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Affiliation(s)
- Daniel L Heringer
- Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, SP, Brazil; Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, United States
| | | | - Jeremy Weleff
- Department of Psychiatry, Yale University School of Medicine, CT, United States; Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, United States; Department of Psychiatry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada; Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
| | - Victor Rodrigues
- Faculdade de Ciências Médicas, Universidade do Estado do Rio de Janeiro, RJ 20950-000, Brazil
| | - Shreya Sengupta
- Department of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, United States.
| | - Akhil Anand
- Department of Psychiatry and Psychology, Cleveland Clinic, Cleveland, United States; Department of Psychiatry, University Hospitals Medical Center, Cleveland, OH, United States.
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7
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Israelsen M, Rungratanawanich W, Thiele M, Liangpunsakul S. Non-invasive tests for alcohol-associated liver disease. Hepatology 2024; 80:1390-1407. [PMID: 38607723 PMCID: PMC11815997 DOI: 10.1097/hep.0000000000000885] [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: 02/24/2024] [Accepted: 03/23/2024] [Indexed: 04/14/2024]
Abstract
Alcohol consumption is a global phenomenon and a major contributor to alcohol-associated liver disease (ALD). Detecting individuals at risk of ALD has been challenging, with only a small fraction of patients being identified at early stages compared to other chronic liver diseases. In response to this challenge, non-invasive tests (NITs) have become essential tools for the detection of ALD, offering opportunities for early identification and intervention to mitigate the disease burden. Noninvasive alcohol consumption biomarkers are crucial in estimating individuals' recent alcohol intake, providing valuable insights into their drinking patterns. Various NITs have been investigated for the initial screening of asymptomatic individuals at risk of ALD, as well as for identifying specific stages of the disease. These NITs are applied in 2 main clinical scenarios: population-based stratification for identifying and predicting liver-related symptoms and diagnosing and prognosticating compensated cirrhosis or advanced chronic liver disease in secondary or tertiary care settings. Moreover, NITs play a significant role in the prognostic assessment of patients with various manifestations of ALD, including alcohol-associated hepatitis (AH), decompensated cirrhosis, and metabolic-associated and ALD. These tests guide appropriate treatment decisions and predict outcomes. In this review, various NITs for the early detection and monitoring of alcohol consumption were discussed. Additionally, the evaluation of NITs for screening and predicting ALD and liver complications was addressed comprehensively. Future perspectives of NITs for ALD were explored, alongside a thorough discussion of the opportunities and challenges associated with NITs for ALD screening.
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Affiliation(s)
- Mads Israelsen
- Fibrosis Fatty Liver and Steatohepatitis Research Centre, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Wiramon Rungratanawanich
- Section of Molecular Pharmacology and Toxicology, National Institute on Alcohol Abuse and Alcoholism, 9000 Rockville Pike, Bethesda, Maryland, USA
| | - Maja Thiele
- Fibrosis Fatty Liver and Steatohepatitis Research Centre, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
- Institute of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
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8
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Anouti A, Kerr TA, Mitchell MC, Cotter TG. Advances in the management of alcohol-associated liver disease. Gastroenterol Rep (Oxf) 2024; 12:goae097. [PMID: 39502523 PMCID: PMC11537353 DOI: 10.1093/gastro/goae097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 09/29/2024] [Accepted: 10/08/2024] [Indexed: 11/08/2024] Open
Abstract
Alcohol-associated liver disease (ALD) is a significant global health challenge, encompassing a spectrum from steatotic liver disease to cirrhosis and alcohol-associated hepatitis, and contributed to 25% of global cirrhosis deaths in 2019. The identification of both modifiable (e.g. heavy drinking, metabolic syndromes) and non-modifiable risk factors (e.g. genetic predispositions) is crucial for effective disease management. Alcohol use assessment and treatment, by using both behavioral therapy and pharmacotherapeutic modalities, nutrition support, and optimization of liver disease modifiers, form the cornerstone of management. Advances in medical therapies, such as fecal microbiota transplantation and novel agents such as IL-22, are being explored for their therapeutic potential. A unifying theme in ALD care is the need for a personalized approach to management, accounting for the spectrum of the disease and individual patient characteristics, to tailor interventions effectively. Finally, it is essential to address the challenges to effective ALD treatment, including socioeconomic, logistical, and stigma-related barriers, to improve patient outcomes. This review discusses the current knowledge on ALD, including epidemiology, pathophysiology, risk factors, and management strategies, highlighting the critical role of integrated care models.
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Affiliation(s)
- Ahmad Anouti
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Thomas A Kerr
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
| | - Thomas G Cotter
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
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9
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Thoudam T, Gao H, Jiang Y, Huda N, Yang Z, Ma J, Liangpunsakul S. Mitochondrial quality control in alcohol-associated liver disease. Hepatol Commun 2024; 8:e0534. [PMID: 39445886 PMCID: PMC11512632 DOI: 10.1097/hc9.0000000000000534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 07/31/2024] [Indexed: 10/25/2024] Open
Abstract
Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.
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Affiliation(s)
- Themis Thoudam
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Hui Gao
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Yanchao Jiang
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nazmul Huda
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Zhihong Yang
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jing Ma
- 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
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
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10
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Witkiewitz K, Fernandez AC, Green EW, Mellinger JL. Diagnosis of Alcohol Use Disorder and Alcohol-Associated Liver Disease. Clin Liver Dis 2024; 28:699-713. [PMID: 39362716 PMCID: PMC11463730 DOI: 10.1016/j.cld.2024.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/05/2024]
Abstract
Harmful alcohol use and alcohol use disorder (AUD) are common worldwide, and rates of alcohol-associated liver disease (ALD) are also increasing. AUD is a disease that is treatable and can be diagnosed and managed, and recovery from AUD through abstinence or reductions in drinking is possible. Management of AUD among individuals with ALD is increasingly being addressed via integrated medical and psychosocial treatment teams that can support reductions in drinking and prevent progression of liver disease. Early diagnosis of AUD and ALD can improve lives and reduce mortality.
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Affiliation(s)
- Katie Witkiewitz
- Center on Alcohol, Substance Use, and Addictions, University of New Mexico, 2650 Yale Boulevard Southeast, Albuquerque, NM 87106, USA.
| | - Anne C Fernandez
- Department of Psychiatry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA
| | - Ellen W Green
- Division of Gastroenterology & Hepatology, University of North Carolina, 130 Mason Farm Road, Bioinformatics Building CB# 7080, Chapel Hill, NC 27599-7080, USA
| | - Jessica L Mellinger
- Department of Psychiatry, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA; Department of Medicine, University of Michigan
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11
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Penrice DD, Jalan-Sakrikar N, Jurk D, Passos JF, Simonetto DA. Telomere dysfunction in chronic liver disease: The link from aging. Hepatology 2024; 80:951-964. [PMID: 37102475 PMCID: PMC10848919 DOI: 10.1097/hep.0000000000000426] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 04/20/2023] [Indexed: 04/28/2023]
Affiliation(s)
- Daniel D. Penrice
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nidhi Jalan-Sakrikar
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Diana Jurk
- Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
| | - João F. Passos
- Department of Physiology and Biomedical Engineering, Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, Minnesota, USA
| | - Douglas A. Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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12
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Danpanichkul P, Chen VL, Chaiyakunapruk N, Auttapracha T, Kongarin S, Ng CH, Duangsonk K, Muthiah MD, Sukphutanan B, Sim B, Huang DQ, Seko Y, Lee BP, Takahashi H, Noureddin M, Lazarus JV, Díaz LA, Arab JP, Mellinger JL, Liangpunsakul S, Wijarnpreecha K. Socio-economic association of alcohol use disorder and cardiovascular and alcohol-associated liver disease from 2010 to 2019. Aliment Pharmacol Ther 2024; 60:340-349. [PMID: 38808961 DOI: 10.1111/apt.18095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/23/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024]
Abstract
BACKGROUNDS AND AIMS Alcohol use leads to disabilities and deaths worldwide. It not only harms the liver but also causes alcohol use disorder (AUD) and heart disease. Additionally, alcohol consumption contributes to health disparities among different socio-economic groups. METHODS We estimated global and regional trends in the burden of AUD, liver disease, and cardiovascular disease from alcohol using the methodology of the Global Burden of Disease study. RESULTS In 2019, the highest disability-adjusted life years rate per 100,000 population was due to AUD (207.31 [95% Uncertainty interval (UI) 163.71-261.66]), followed by alcohol-associated liver disease (ALD) (133.31 [95% UI 112.68-156.17]). The prevalence rate decreased for AUD (APC [annual percentage change] -0.38%) and alcohol-induced cardiomyopathy (APC -1.85%) but increased for ALD (APC 0.44%) and liver cancer (APC 0.53%). Although the mortality rate for liver cancer from alcohol increased (APC 0.30%), mortality rates from other diseases decreased. Between 2010 and 2019, the burden of alcohol-associated complications increased in countries with low and low-middle sociodemographic index (SDI), contributing more significantly to the global burden. CONCLUSION The global burden of AUD, liver, and cardiovascular disease has been high and increasing over the past decade, particularly for liver complications. Lower SDI countries are contributing more to this global burden. There is a pressing need for effective strategies to address this escalating burden.
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Affiliation(s)
- Pojsakorn Danpanichkul
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
- Immunology Unit, Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Nathorn Chaiyakunapruk
- Department of Pharmacotherapy, College of Pharmacy, University of Utah, Salt Lake City, Utah, USA
- IDEAS Center, Veterans Affairs Salt Lake City Healthcare System, Salt Lake City, Utah, USA
| | | | | | - Cheng Han Ng
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Kwanjit Duangsonk
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Mark D Muthiah
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | | | - Benedix Sim
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
| | - Daniel Q Huang
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Health System, Singapore
- MASLD Research Center, Division of Gastroenterology, University of California at San Diego, San Diego, California, USA
| | - Yuya Seko
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto, Japan
| | - Brian P Lee
- Division of Gastroenterology and Liver Diseases, University of Southern California, Los Angeles, California, USA
| | - Hirokazu Takahashi
- Division of Metabolism and Endocrinology, Faculty of Medicine, Saga University, Saga, Japan
| | - Mazen Noureddin
- Houston Research Institute and Houston Methodist Hospital, Houston, Texas, USA
| | - Jeffrey V Lazarus
- CUNY Graduate School of Public Health and Health Policy (CUNY SPH), New York, New York, USA
- Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain
- Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain
- The Global NASH Council, Washington, DC, USA
| | - Luis Antonio Díaz
- MASLD Research Center, Division of Gastroenterology, University of California at San Diego, San Diego, California, USA
- The Global NASH Council, Washington, DC, USA
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
- Observatorio Multicéntrico de Enfermedades Gastrointestinales, OMEGA, Santiago, Chile
| | - Juan Pablo Arab
- Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Catolica de Chile, Santiago, Chile
- Observatorio Multicéntrico de Enfermedades Gastrointestinales, OMEGA, 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
| | - Jessica Leigh Mellinger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine, Phoenix, Arizona, USA
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Banner University Medical Center, Phoenix, Arizona, USA
- BIO5 Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
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13
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Danpanichkul P, Chen VL, Tothanarungroj P, Kaewdech A, Kanjanakot Y, Fangsaard P, Wattanachayakul P, Duangsonk K, Kongarin S, Yang JD, Wong RJ, Noureddin M, Díaz LA, Arab JP, Liangpunsakul S, Wijarnpreecha K. Global epidemiology of alcohol-associated liver disease in adolescents and young adults. Aliment Pharmacol Ther 2024; 60:378-388. [PMID: 38828940 DOI: 10.1111/apt.18101] [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: 04/19/2024] [Revised: 05/10/2024] [Accepted: 05/22/2024] [Indexed: 06/05/2024]
Abstract
BACKGROUND AND AIMS The objective of the study was to analyse the prevalence, incidence, and death of alcohol-associated liver disease (ALD) among adolescents and young adults globally, continentally, and nationally, focusing on trends over time. METHODS The study analysed data from the Global Burden of Disease (GBD) study between 2000 and 2019. It examined ALD's prevalence, incidence, and death in adolescents and young adults aged 15-29, segmented by region, nation, and sociodemographic index. The analysis utilised Joinpoint regression modelling to calculate the annual per cent change (APC) in the rate of these parameters over time. RESULTS In 2019, there were 281,450 ALD prevalences, 18,930 incidences, and 3190 deaths among adolescents and young adults globally. From 2000 to 2019, the age-adjusted prevalence rate per 100,000 increased in the 25-29 age group (APC: +0.6%, p = 0.003), remained stable among ages 20-24 (p = 0.302) and ages 15-19 (p = 0.160). Prevalence increased significantly from age 15-19 to 20-24 (19-fold increase) and from age 20-24 to 25-29 (2.5-fold increase). ALD prevalence rates increased in all age groups in adolescents and young adults in Africa and the Eastern Mediterranean region. Around three-quarters of countries and territories experienced an increase in ALD incidence rates in young adults. CONCLUSION Over two decades, the burden of ALD among adolescents and young adults has increased globally. The study emphasises the importance of public health policies aimed at reducing alcohol consumption and preventing ALD among younger populations.
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Affiliation(s)
- Pojsakorn Danpanichkul
- Immunology Unit, Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Vincent L Chen
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | | | - Apichat Kaewdech
- Gastroenterology and Hepatology Unit, Division of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkhla, Thailand
| | - Yatawee Kanjanakot
- Department of Surgery, School of Medicine, Mae Fah Luang University, Chiang Rai, Thailand
| | - Panisara Fangsaard
- Department of Internal Medicine, Bassett Medical Center, Cooperstown, New York, USA
| | | | - Kwanjit Duangsonk
- Department of Microbiology, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand
| | | | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Comprehensive Transplant Center, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA
| | - Robert J Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Palo Alto, California, USA
- Gastroenterology Section, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | - Mazen Noureddin
- Houston Research Institute and Houston Methodist Hospital, Houston, Texas, USA
| | - Luis Antonio Díaz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Observatorio Multicéntrico de Enfermedades Gastrointestinales, OMEGA, Santiago, Chile
- MASLD Research Center, Division of Gastroenterology, University of California, San Diego, California, USA
- The Global NASH Council, Washington, The District Of Columbia, USA
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
- Observatorio Multicéntrico de Enfermedades Gastrointestinales, OMEGA, 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
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans' Administration Medical Center, Indianapolis, Indiana, USA
| | - Karn Wijarnpreecha
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
- Department of Internal Medicine, Banner-University Medical Center, Phoenix, Arizona, USA
- BIO5 Institute, University of Arizona College of Medicine-Phoenix, Phoenix, Arizona, USA
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14
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Floris A, Chandla S, Lim Y, Barbier-Torres L, Seth K, Khangholi A, Li TW, Robison A, Murray BJ, Lee S, Michitaka M, Murali R, Tomasi ML, Lu SC. Sumoylation of methionine adenosyltransferase alpha 1 promotes mitochondrial dysfunction in alcohol-associated liver disease. Hepatology 2024; 80:102-118. [PMID: 38100286 PMCID: PMC11178676 DOI: 10.1097/hep.0000000000000717] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2023] [Accepted: 11/17/2023] [Indexed: 12/17/2023]
Abstract
BACKGROUND AND AIMS Methionine adenosyltransferase alpha1 (MATα1) is responsible for the biosynthesis of S-adenosylmethionine in normal liver. Alcohol consumption enhances MATα1 interaction with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which blocks MATα1 mitochondrial targeting, resulting in lower mitochondrial MATα1 content and mitochondrial dysfunction in alcohol-associated liver disease (ALD) in part through upregulation of cytochrome P450 2E1. Conversely, alcohol intake enhances SUMOylation, which enhances cytochrome P450 2E1 expression. MATα1 has potential SUMOylation sites, but whether MATα1 is regulated by SUMOylation in ALD is unknown. Here, we investigated if MATα1 is regulated by SUMOylation and, if so, how it impacts mitochondrial function in ALD. APPROACH AND RESULTS Proteomics profiling revealed hyper-SUMOylation of MATα1, and prediction software identified lysine 48 (K48) as the potential SUMOylation site in mice (K47 in humans). Experiments with primary hepatocytes, mouse, and human livers revealed that SUMOylation of MAT1α by SUMO2 depleted mitochondrial MATα1. Furthermore, mutation of MATα1 K48 prevented ethanol-induced mitochondrial membrane depolarization, MATα1 depletion, and triglyceride accumulation. Additionally, CRISPR/CRISPR associated protein 9 gene editing of MATα1 at K48 hindered ethanol-induced MATα1-PIN1 interaction, degradation, and phosphorylation of MATα1 in vitro. In vivo, CRISPR/CRISPR associated protein 9 MATα1 K48 gene-edited mice were protected from ethanol-induced fat accumulation, liver injury, MATα1-PIN1 interaction, mitochondrial MATα1 depletion, mitochondrial dysfunction, and low S-adenosylmethionine levels. CONCLUSIONS Taken together, our findings demonstrate an essential role for SUMOylation of MATα1 K48 for interaction with PIN1 in ALD. Preventing MATα1 K48 SUMOylation may represent a potential treatment strategy for ALD.
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Affiliation(s)
- Andrea Floris
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Swati Chandla
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Youngyi Lim
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Lucia Barbier-Torres
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Karina Seth
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Arash Khangholi
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Tony W.H. Li
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Aaron Robison
- Advanced Clinical Biosystems Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ben J. Murray
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Sion Lee
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Matsuda Michitaka
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Ramachandran Murali
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Maria Lauda Tomasi
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Shelly C Lu
- Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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15
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Heilig M, Witkiewitz K, Ray LA, Leggio L. Novel medications for problematic alcohol use. J Clin Invest 2024; 134:e172889. [PMID: 38828724 PMCID: PMC11142745 DOI: 10.1172/jci172889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/05/2024] Open
Abstract
Alcohol-related harm, a major cause of disease burden globally, affects people along a spectrum of use. When a harmful pattern of drinking is present in the absence of significant behavioral pathology, low-intensity brief interventions that provide information about health consequences of continued use provide large health benefits. At the other end of the spectrum, profound behavioral pathology, including continued use despite knowledge of potentially fatal consequences, warrants a medical diagnosis, and treatment is strongly indicated. Available behavioral and pharmacological treatments are supported by scientific evidence but are vastly underutilized. Discovery of additional medications, with a favorable balance of efficacy versus safety and tolerability can improve clinical uptake of treatment, allow personalized treatment, and improve outcomes. Here, we delineate the clinical conditions when pharmacotherapy should be considered in relation to the main diagnostic systems in use and discuss clinical endpoints that represent meaningful clinical benefits. We then review specific developments in three categories of targets that show promise for expanding the treatment toolkit. GPCRs remain the largest category of successful drug targets across contemporary medicine, and several GPCR targets are currently pursued for alcohol-related indications. Endocrine systems are another established category, and several promising targets have emerged for alcohol indications. Finally, immune modulators have revolutionized treatment of multiple medical conditions, and they may also hold potential to produce benefits in patients with alcohol problems.
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Affiliation(s)
- Markus Heilig
- Center for Social and Affective Neuroscience, Linköping University, and Department of Psychiatry, Linköping University Hospital, Linköping, Sweden
| | - Katie Witkiewitz
- Department of Psychology and Center on Alcohol, Substance Use and Addictions, University of New Mexico, Albuquerque, New Mexico, USA
| | - Lara A. Ray
- Department of Psychology, UCLA, Los Angeles, California, USA
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, NIH, Baltimore and Bethesda, Maryland, USA
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Ramirez-Cadiz C, Blaney H, Kubanek N, Díaz LA, Loomba R, Skladany L, Arab JP. Review article: Current indications and selection criteria for early liver transplantation in severe alcohol-associated hepatitis. Aliment Pharmacol Ther 2024; 59:1049-1061. [PMID: 38475893 DOI: 10.1111/apt.17948] [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: 10/17/2023] [Revised: 10/17/2023] [Accepted: 03/03/2024] [Indexed: 03/14/2024]
Abstract
BACKGROUND Alcohol-associated hepatitis (AH) is a severe inflammatory form of alcohol-associated liver disease (ALD) that carries a high mortality rate. Early liver transplantation for severe AH is increasingly available. However, specific criteria for referral and selection remain a subject of debate. AIMS To provide a narrative review of the natural history, diagnostic criteria and indications for referral for early liver transplantation for severe AH. METHODS We searched PubMed for articles published through August 2023. Key search terms were 'alcoholic hepatitis,' 'alcohol-associated hepatitis,' 'abstinence,' 'alcohol relapse,' and 'liver transplantation.' RESULTS Previously, a six-month period of alcohol abstinence was required before patients with ALD were considered for liver transplantation. However, studies in recent years have demonstrated that, among carefully selected patients, patients who received early transplants have much higher survival rates than patients with similarly severe disease who did not undergo transplants (77% vs. 23%). Despite these successes, early liver transplantation remains controversial, as these patients have typically not undergone treatment for alcohol use disorder, with the ensuing risk of returning to alcohol use. CONCLUSIONS While early liver transplantation for AH has survival benefits, many patients would not have received treatment for alcohol use disorder. An integrated approach to evaluating candidacy for early liver transplantation is needed.
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Affiliation(s)
- Carolina Ramirez-Cadiz
- Department of Anesthesia and Perioperative Medicine, Schulich School of Medicine, Western University & London Health Sciences Centre, London, Ontario, Canada
| | - Hanna Blaney
- Division of Gastroenterology and Hepatology, University of Maryland, College Park, Maryland, USA
| | - Natalia Kubanek
- Division of Hepatology, Gastroenterology and Liver Transplantation, Department of Internal Medicine II, Slovak Medical University Faculty of Medicine, F. D. Roosevelt University Hospital, Banska Bystrica, Slovak Republic
| | - Luis Antonio Díaz
- Departamento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Rohit Loomba
- Division of Gastroenterology, University of California at San Diego, San Diego, California, USA
| | - Lubomir Skladany
- Division of Hepatology, Gastroenterology and Liver Transplantation, Department of Internal Medicine II, Slovak Medical University Faculty of Medicine, F. D. Roosevelt University Hospital, Banska Bystrica, Slovak Republic
| | - Juan Pablo Arab
- Departamento de Gastroenterología, Escuela de Medicina, 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
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17
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Cooper KM, Colletta A, Hebda N, Devuni D. Alcohol associated liver disease and bariatric surgery: Current perspectives and future directions. World J Gastrointest Surg 2024; 16:650-657. [PMID: 38577096 PMCID: PMC10989338 DOI: 10.4240/wjgs.v16.i3.650] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/27/2024] [Accepted: 02/26/2024] [Indexed: 03/22/2024] Open
Abstract
Bariatric surgery is a routinely performed procedure and is associated with a reduction in all-cause mortality in patients with obesity. However, bariatric surgery has also been linked to increased alcohol use with up to 30% of these patients developing alcohol use disorder (AUD). The mechanism of AUD after bariatric surgery is multifactorial and includes anatomic, metabolic, and neurohumoral changes associated with post-surgical anatomy. These patients are at increased risk of alcohol associated liver disease and, in some cases, require liver transplantation. In this article, we provide a scoping review of epidemiology, pathophysiology, and clinical outcomes of alcohol-related health conditions after bariatric surgery.
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Affiliation(s)
- Katherine M Cooper
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
| | - Alessandro Colletta
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
| | - Nicholas Hebda
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
| | - Deepika Devuni
- Department of Medicine, UMass Chan Medical School, Worcester, MA 01655, United States
- Division of Gastroenterology, UMass Chan Medical School, Worcester, MA 01655, United States
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18
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Marlowe N, Lam D, Liangpunsakul S. Epidemic within a pandemic: Alcohol-associated hepatitis and COVID-19. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2023; 47:1883-1889. [PMID: 37553753 DOI: 10.1111/acer.15162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 07/28/2023] [Indexed: 08/10/2023]
Abstract
BACKGROUND There was an increase in alcoholic beverage sales during the peak of the COVID pandemic in the United States. However, little is known about the impact of SARS-CoV-2 infection among hospitalized alcohol-associated hepatitis (AH) patients. METHODS We analyzed the available National Inpatient Data (NIS) data from 2020 to determine mortality and healthcare utilization among hospitalized AH patients with and without COVID-19 in the United States. RESULTS We observed a ~15.6% increase in cases of hospitalized AH patients from 136,620 in 2019 to 157,885 in 2020, a significant increase from an average of 5.5% per annum despite an 8.7% decline in US hospital admissions over the same time span. Men younger than 40 were the fastest growing AH group, with a 23% increase in 2020. Approximately 1.8% of hospitalized AH patients had a SARS-CoV-2 infection, which significantly worsened the mortality among patients with AH (11.4% vs. 4.1%, p < 0.0001). This was especially true among older AH patients with concomitant conditions such as clinically apparent cirrhosis, acute renal failure, upper gastrointestinal bleeding, and sepsis. AH patients with COVID-19 also had a longer length of stay (8.6 vs. 6.1 days, p < 0.0001) and higher hospital charges during the stay ($93,670 vs. $66,283, p < 0.0001) than those without COVID-19. CONCLUSION Our study highlights the rise in AH cases during the COVID-19 pandemic. Screening and appropriate management of excessive alcohol use and preventive measures such as COVID-19 vaccination should be considered to reduce morbidity and mortality among patients with AH.
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Affiliation(s)
| | - David Lam
- Pharma Analytics, San Anselmo, California, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
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19
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Abstract
Clinical trials have been a central driver of change and have provided the evidence base necessary to advance new therapies for liver diseases. This review provides a perspective on the status of trials in hepatology and a vantage point into the emerging capabilities and external forces that will shape the conduct of clinical trials in the future. The adaptations to clinical trial operations in response to the disruptions by the COVID-19 pandemic and opportunities for innovation in hepatology trials are emphasized. Future trials in hepatology will be driven by unmet therapeutic needs and fueled by technological advances incorporating digital capabilities with expanded participant-derived data collection, computing, and analytics. Their design will embrace innovative trial designs adapted to these advances and that emphasize broader and more inclusive participant engagement. Their conduct will be further shaped by evolving regulatory needs and the emergence of new stakeholders in the clinical trials ecosystem. The evolution of clinical trials will offer unique opportunities to advance new therapeutics that will ultimately improve the lives of patients with liver diseases.
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Affiliation(s)
- Paul Y Kwo
- Department of Medicine, Stanford University School of Medicine, Palo Alto, California, USA
| | - Tushar Patel
- Department of Transplantation, Mayo Clinic, Jacksonville, Florida, USA
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20
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Alkhuder K. Raman Scattering-Based Optical Sensing Of Chronic Liver Diseases. Photodiagnosis Photodyn Ther 2023; 42:103505. [PMID: 36965755 DOI: 10.1016/j.pdpdt.2023.103505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Revised: 02/26/2023] [Accepted: 03/07/2023] [Indexed: 03/27/2023]
Abstract
Chronic liver diseases (CLDs) are a major public health problem. Despite the progress achieved in fighting against viral hepatitis, the emergence of non-alcoholic fatty liver disease might pose a serious challenge to the public's health in the coming decades. Medical management of CLDs represents a substantial burden on the public health infrastructures. The health care cost of these diseases is an additional burden that weighs heavily on the economies of developing countries. Effective management of CLDs requires the adoption of reliable and cost-effective screening and diagnosing methods to ensure early detection and accurate clinical assessment of these diseases. Vibrational spectroscopies have emerged as universal analytical methods with promising applications in various industrial and biomedical fields. These revolutionary analytical techniques rely on analyzing the interaction between a light beam and the test sample to generate a spectral fingerprint. This latter is defined by the analyte's chemical structure and the molecular vibrations of its functional groups. Raman spectroscopy and surface-enhanced Raman spectroscopy have been used in combination with various chemometric tests to diagnose a wide range of malignant, metabolic and infectious diseases. The aim of the current review is to cast light on the use of these optical sensing methods in the diagnosis of CLDs. The vast majority of research works that investigated the potential application of these spectroscopic techniques in screening and detecting CLDs were discussed here. The advantages and limitations of these modern analytical methods, as compared with the routine and gold standard diagnostic approaches, were also reviewed in details.
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21
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Xiao Y, Zhao C, Tai Y, Li B, Lan T, Lai E, Dai W, Guo Y, Gan C, Kostallari E, Tang C, Gao J. STING mediates hepatocyte pyroptosis in liver fibrosis by Epigenetically activating the NLRP3 inflammasome. Redox Biol 2023; 62:102691. [PMID: 37018971 PMCID: PMC10106968 DOI: 10.1016/j.redox.2023.102691] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 03/11/2023] [Accepted: 03/28/2023] [Indexed: 03/31/2023] Open
Abstract
The activation of stimulator of interferon genes (STING) and NOD-like receptor protein 3 (NLRP3) inflammasome-mediated pyroptosis signaling pathways represent two distinct central mechanisms in liver disease. However, the interconnections between these two pathways and the epigenetic regulation of the STING-NLRP3 axis in hepatocyte pyroptosis during liver fibrosis remain unknown. STING and NLRP3 inflammasome signaling pathways are activated in fibrotic livers but are suppressed by Sting knockout. Sting knockout ameliorated hepatic pyroptosis, inflammation, and fibrosis. In vitro, STING induces pyroptosis in primary murine hepatocytes by activating the NLRP3 inflammasome. H3K4-specific histone methyltransferase WD repeat-containing protein 5 (WDR5) and DOT1-like histone H3K79 methyltransferase (DOT1L) are identified to regulate NLRP3 expression in STING-overexpressing AML12 hepatocytes. WDR5/DOT1L-mediated histone methylation enhances interferon regulatory transcription factor 3 (IRF3) binding to the Nlrp3 promoter and promotes STING-induced Nlrp3 transcription in hepatocytes. Moreover, hepatocyte-specific Nlrp3 deletion and downstream Gasdermin D (Gsdmd) knockout attenuate hepatic pyroptosis, inflammation, and fibrosis. RNA-sequencing and metabolomics analysis in murine livers and primary hepatocytes show that oxidative stress and metabolic reprogramming might participate in NLRP3-mediated hepatocyte pyroptosis and liver fibrosis. The STING-NLRP3-GSDMD axis inhibition suppresses hepatic ROS generation. In conclusion, this study describes a novel epigenetic mechanism by which the STING-WDR5/DOT1L/IRF3-NLRP3 signaling pathway enhances hepatocyte pyroptosis and hepatic inflammation in liver fibrosis.
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22
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Aslam A, Kwo PY. Epidemiology and Disease Burden of Alcohol Associated Liver Disease. J Clin Exp Hepatol 2023; 13:88-102. [PMID: 36647400 PMCID: PMC9840073 DOI: 10.1016/j.jceh.2022.09.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 09/06/2022] [Indexed: 01/19/2023] Open
Abstract
Consumption of alcohol in excess leads to substantial medical, economic, and societal burdens. Approximately 5.3% of all global deaths may be attributed to alcohol consumption. Moreover, the burden of alcohol associated liver disease (ALD) accounts for 5.1% of all disease and injury worldwide. Alcohol use disorder (AUD) affects men more than women globally with significant years of life loss to disability in low, middle and well-developed countries. Precise data on global estimates of alcohol related steatosis, alcohol related hepatitis, and alcohol related cirrhosis have been challenging to obtain. In the United States (US), alcohol related steatosis has been estimated at 4.3% based on NHANES data which has remained stable over 14 years. However, alcohol-related fibrotic liver disease has increased over the same period. In those with AUD, the prevalence of alcohol related hepatitis has been estimated at 10-35%. Globally, the prevalence of alcohol-associated cirrhosis has been estimated at 23.6 million individuals for compensated cirrhosis and 2.46 million for those with decompensated cirrhosis. The contribution of ALD to global mortality and disease burden of liver related deaths is substantial. In 2016 liver disease related to AUD contributed to 50% of the estimated liver disease deaths for age groups 15 years and above. Data from the US report high cost burdens associated with those admitted with alcohol-related liver complications. Finally, the recent COVID-19 pandemic has been associated with marked increase in alcohol consumption worldwide and will likely increase the burden of ALD.
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Key Words
- AAPC, Average annual percentage change
- ABIC, Age, Serum bilirubin, INR and serum Creatinine
- ABV, Alcohol by volume
- ALD, Alcohol-associated liver disease
- AUD, Alcohol use disorder
- BAC, Blood alcohol concentration
- CDC, Centers for Disease Control and Prevention
- COVID-19, Coronavirus disease 2019
- GAHS, Glasgow alcoholic hepatitis score
- HE, Hepatic encephalopathy
- HRS, Hepatorenal syndrome
- ICD-10, International Classification of Diseases, 10th Edition
- MDF, Maddrey's Discriminant Function
- MELD, Model of end-stage liver disease
- MRI, Magnetic resonance imaging
- NHANES, National Health and Nutrition Examination Survey
- NIAAA, National Institute of Alcohol Abuse and Alcoholism
- NIS, National inpatient sample
- NSDUH, Annual National Survey on Drug Use and Health
- SAMHSA, Substance Abuse and Mental Health Services Administration
- US, United States
- USG, Ultrasonography
- WHO, World Health Organization
- YLD, Years of life lost to disability
- alcohol
- alcohol use disorder
- alcoholic cirrhosis
- alcoholic hepatitis
- alcoholic steatosis
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Affiliation(s)
- Aysha Aslam
- Stanford University School of Medicine, 430 Broadway, Pavilion C, 3rd Floor, Redwood City, CA 94063, USA
| | - Paul Y. Kwo
- Stanford University School of Medicine, 430 Broadway, Pavilion C, 3rd Floor, Redwood City, CA 94063, USA
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23
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Liu YB, Chen MK. Epidemiology of liver cirrhosis and associated complications: Current knowledge and future directions. World J Gastroenterol 2022; 28:5910-5930. [PMID: 36405106 PMCID: PMC9669831 DOI: 10.3748/wjg.v28.i41.5910] [Citation(s) in RCA: 62] [Impact Index Per Article: 20.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Revised: 09/30/2022] [Accepted: 10/20/2022] [Indexed: 02/06/2023] Open
Abstract
Cirrhosis causes a heavy global burden. In this review, we summarized up-to-date epidemiological features of cirrhosis and its complications. Recent epidemiological studies reported an increase in the prevalence of cirrhosis in 2017 compared to in 1990 in both men and women, with 5.2 million cases of cirrhosis and chronic liver disease occurring in 2017. Cirrhosis caused 1.48 million deaths in 2019, an increase of 8.1% compared to 2017. Disability-adjusted life-years due to cirrhosis ranked 16th among all diseases and 7th in people aged 50-74 years in 2019. The global burden of hepatitis B virus and hepatitis C virus-associated cirrhosis is decreasing, while the burden of cirrhosis due to alcohol and nonalcoholic fatty liver disease (NAFLD) is increasing rapidly. We described the current epidemiology of the major complications of cirrhosis, including ascites, variceal bleeding, hepatic encephalopathy, renal disorders, and infections. We also summarized the epidemiology of hepatocellular carcinoma in patients with cirrhosis. In the future, NAFLD-related cirrhosis will likely become more common due to the prevalence of metabolic diseases such as obesity and diabetes, and the prevalence of alcohol-induced cirrhosis is increasing. This altered epidemiology should be clinically noted, and relevant interventions should be undertaken.
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Affiliation(s)
- Yuan-Bin Liu
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
| | - Ming-Kai Chen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430000, Hubei Province, China
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24
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Liu J, Kong L, Shao M, Sun C, Li C, Wang Y, Chai X, Wang Y, Zhang Y, Li X, Zhao H. Seabuckthorn polysaccharide combined with astragalus polysaccharide ameliorate alcoholic fatty liver by regulating intestinal flora. Front Endocrinol (Lausanne) 2022; 13:1018557. [PMID: 36246879 PMCID: PMC9559367 DOI: 10.3389/fendo.2022.1018557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 09/02/2022] [Indexed: 11/30/2022] Open
Abstract
Background At present, the incidence of alcoholic fatty liver disease (AFLD) is increasing year by year, and numerous studies have confirmed that liver diseases are closely related to intestinal flora. Seabuckthorn and Astragalus membranaceus, as traditional Chinese medicine (TCM) with the homology of medicine and food, have good liver protection, and their polysaccharides can regulate the intestinal flora. Here, we studied the effects of HRP, APS and the combination of the two polysaccharides on the intestinal flora of AFLD mice, which provided scientific basis for the treatment of AFLD with the two polysaccharides. Materials and methods Thirty Kunming (KM) mice were randomly divided into the control group (Con), the model group (Mod), the HRP treatment group (HRP), the APS treatment group (APS), and HRP+APS treatment group (HRP+APS), with six mice in each group. The AFLD model was constructed by continuous intragastric administration of 42% vol Niulanshan ethanol solution for 28 days, and the mice in each polysaccharide group were given corresponding drugs. The levels of AST, ALT, TC and TG in serum of mice were measured. 16S rRNA amplicon sequencing technique was used to determine the diversity and richness of intestinal flora, and the relative abundance of intestinal flora at phylum level and genus level of the mice in each group. Results HRP, APS and HRP+APS could reduce the serum levels of AST, ALT, TC and TG in mice. In addition, HRP, APS and HRP + APS restored the diversity, relative abundance and community structure of intestinal mucosa bacteria in AFLD mice to a certain extent. Specifically, HRP, APS and HRP+APS remarkably decreased the ratio of Firmicutes to Bacteroidetes, and ultimately increased the abundance of beneficial bacteria and reduced the abundance of pathogenic bacteria. Conclusion HRP, APS, and HRP+APS can improve the intestinal microecology of AFLD model mice, alleviate liver injury, and maintain normal intestinal function in different degrees.
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Affiliation(s)
- Jiayue Liu
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Lingzhou Kong
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Mengting Shao
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Changhai Sun
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Changxu Li
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Yanyan Wang
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Xue Chai
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Yuliang Wang
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Yu Zhang
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
| | - Xiaoliang Li
- Key Laboratory of Tropical Translational Medicine of Ministry of Education, Hainan Provincial Key Laboratory for Research and Development of Tropical Herbs, Haikou Key Laboratory of Li Nationality Medicine, School of Pharmacy, Hainan Medical University, Haikou, China
| | - Hong Zhao
- College of Pharmacy, Heilongjiang Provincial Key Laboratory of New Drug Development and Pharmacotoxicological Evaluation, Jiamusi University, Jiamusi, China
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25
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Fang J, Wu Y, Gan C, Ruan S, He X, Wang B, Wang Y, Yu J, Sang C, Zeren D, Xiong T. Jia-ga-song-tang protection against alcoholic liver and intestinal damage. Front Pharmacol 2022; 13:981706. [PMID: 36225559 PMCID: PMC9549243 DOI: 10.3389/fphar.2022.981706] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Gut-liver axis and cellular homeostasis play key roles in alcohol liver disease (ALD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a stress-sensitive guarantor of cellular homeostasis. We investigated whether the beneficial effects and underlying mechanisms of Jia-ga-song Tang (JGST) against ALD were associated with gut-liver axis and cellular homeostasis. A predictive network depicting the relationship between Jia-Ga-Song-Tang (JGST) and alcoholic liver disease (ALD) was designed by Network pharmacology. Next, 5% v/v Lieber-DeCarli alcohol liquid diet was used to establish the ALD. JGST protected the liver damage, repaired the intestines to alleviate the Two-hit on the liver, and balanced the cellular homeostasis. It was manifested in repairing the liver and intestinal pathological structure, reducing serum ALT, AST, and liver TG, TC, MDA, CAT, and increasing liver GSH, and intestine GSH-Px. JGST mainly inhibited the liver mRNA levels of HO-1, NQO1, GCLC, FASN, and PPARα and activated the intestinal mRNA levels of HO-1 and NQO1, while inhibiting the liver protein levels of HO-1, NQO1. Furthermore, LPS and LBP in the plasma and the expression of inflammatory factors such as IL-1β, TNF-α, IL-6, TGFβ1, CD14, and Myd88 were reduced after treatment to prove that JGST protects the liver from Two-hit. Ethanol was used to intervene in HepG2 and IEC-6 to establish an ALD cell model and treated by Germacrone, ML385, and TBHQ. repaired the intestinal barrier, and inhibited Nrf2 in IEC-6, but protect the HepG2 by activating Nrf2 to balance cellular homeostasis. Our results reinforce that JGST provides an effective protective method for alcoholic liver disease (ALD) by regulating Gut-liver axis and cellular homeostasis.
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Affiliation(s)
- Jiamin Fang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yuhuan Wu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Changlian Gan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shufang Ruan
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xiaoliang He
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Bixia Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Ying Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jingtao Yu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Chuanlan Sang
- Laboratory of Experimental Animal, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Tianqin Xiong, ; Chuanlan Sang, ; Dawa Zeren,
| | - Dawa Zeren
- Research Department, University of Tibetan Medicine, Lhasa, China
- *Correspondence: Tianqin Xiong, ; Chuanlan Sang, ; Dawa Zeren,
| | - Tianqin Xiong
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China
- *Correspondence: Tianqin Xiong, ; Chuanlan Sang, ; Dawa Zeren,
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26
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Huda N, Kusumanchi P, Perez K, Jiang Y, Skill NJ, Sun Z, Ma J, Yang Z, Liangpunsakul S. Telomere length in patients with alcohol-associated liver disease: a brief report. J Investig Med 2022; 70:1438-1441. [PMID: 35246468 PMCID: PMC9378353 DOI: 10.1136/jim-2021-002213] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/16/2022] [Indexed: 01/17/2023]
Abstract
The intact telomere structure is essential for the prevention of the chromosome end-to-end fusions and maintaining genomic integrity. The maintenance of telomere length is critical for cellular homeostasis. The shortening of telomeres has been reported in patients with chronic liver diseases. The telomere length has not been systemically studied in patients with alcohol-associated liver disease (ALD) at different stages, such as alcoholic hepatitis and alcoholic cirrhosis. In this brief report, we observed evidence of telomere shortening without changes in the telomerase activity in the liver of patients with alcoholic hepatitis and alcoholic cirrhosis when compared with controls. The alterations in the genes associated with telomere binding proteins were only observed in patients with alcoholic cirrhosis. Future studies are required to determine the mechanism of how alcohol affects the length of the telomere and if the shortening impacts the disease progression in ALD.
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Affiliation(s)
- Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Kristina Perez
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Nicholas J Skill
- Department of Surgery, Louisiana State University Health Science Center, New Orleans, LA, USA
| | - Zhaoli Sun
- Department of Surgery, Johns Hopkins University School of Medicine, Baltiore, MD, USA
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA
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27
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Marlowe N, Lam D, Krebs W, Lin W, Liangpunsakul S. Prevalence, co-morbidities, and in-hospital mortality of patients hospitalized with alcohol-associated hepatitis in the United States from 2015 to 2019. Alcohol Clin Exp Res 2022; 46:1472-1481. [PMID: 35778777 DOI: 10.1111/acer.14896] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 05/29/2022] [Accepted: 06/24/2022] [Indexed: 01/31/2023]
Abstract
BACKGROUND The goals of our study are to determine the most recent trends in hospitalization, mortality, and healthcare utilization among hospitalized patients with alcohol-associated hepatitis (AH) in the United States. METHODS We examined the recent prevalence, co-morbidities, and mortality in hospitalized AH patients in the United States based on the available National Inpatient Sample (NIS) data (2015 to 2019) using appropriate International Classification of Diseases (ICD) codes. We reported our data as national estimates based on the discharge weighting variable (DISCWT). Logistic regression analyses were used to determine factors associated with mortality. RESULTS We observed an increase in the total number of hospitalized AH patients from 110,135 in 2015 to 136,620 in 2019, which represented 386 per 100,000 total hospitalizations or 42 per 100,000 US population, which in 2019 was 328 million. Patients were a mean of 48 years old and the majority were White and male. The average length of stay was around 6 days with an overall in-hospital mortality that decreased from 4.19% in 2015 to 3.86% in 2019 (p-value for trend = <0.0001). During the 5-year study period, a total of 24,795 hospitalized AH patients died and 592,885 survived the hospital stay. Those who died were older, had a longer length of stay, and higher hospital charges during the stay. Mortality was significantly greater in patients who presented with complications from portal hypertension, those with acute renal failure, underlying cirrhosis, and sepsis. CONCLUSIONS Our study documented the increasing prevalence of hospitalized AH patients and their significant associated healthcare costs and utilization. Our results underscore a continuing unmet and urgent need to identify effective therapies for hospitalized AH patients.
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Affiliation(s)
| | - David Lam
- Pharma Analytics, San Anselmo, California, USA
| | - William Krebs
- William B, Krebs Consulting Statistician, San Francisco, California, USA
| | - WeiQi Lin
- Durect Corporation, Cupertino, California, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University, Indianapolis, Indiana, USA
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miR-29c-3p promotes alcohol dehydrogenase gene cluster expression by activating an ADH6 enhancer. Biochem Pharmacol 2022; 203:115182. [PMID: 35868429 DOI: 10.1016/j.bcp.2022.115182] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 07/13/2022] [Accepted: 07/14/2022] [Indexed: 12/18/2022]
Abstract
Alcohol dehydrogenases (ADHs) play vital roles in alcohol metabolism and alcohol toxicity, yet little is known about microRNA-mediated regulation of the ADH gene cluster. Here, we showed that miR-29c activated ADH gene cluster transcription by targeting an enhancer element within the ADH6 gene. miR-29c is differentially expressed in alcoholic liver disease. Following biochemical and molecular evidence demonstrated that miR-29c increased ADH6 mRNA and protein levels without affecting the stability of the ADH6 transcript. Further evidence showed that exogenous miR-29c translocated into the nucleus and then unconventionally bound an enhancer element within the ADH6 gene. Luciferase reporter assay and chromatin immunoprecipitation data indicated that miR-29c activated the enhancer and increased the enrichment of RNA polymerase II at the promoter regions of ADH1A, ADH1B, ADH1C, ADH4, and ADH6. Finally, exogenous miR-29c transfection promoted the expression of ADH1A, ADH1B, ADH1C, and ADH4 pre-mRNA and mRNA transcripts from the ADH gene cluster. In conclusion, our data suggest that miR-29c might be a novel epigenetic regulator involved in ADH gene cluster activation.
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Ferdouse A, Clugston RD. Pathogenesis of Alcohol-Associated Fatty Liver: Lessons From Transgenic Mice. Front Physiol 2022; 13:940974. [PMID: 35864895 PMCID: PMC9294393 DOI: 10.3389/fphys.2022.940974] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/15/2022] [Indexed: 12/18/2022] Open
Abstract
Alcohol-associated liver disease (ALD) is a major public health issue that significantly contributes to human morbidity and mortality, with no FDA-approved therapeutic intervention available. The health burden of ALD has worsened during the COVID-19 pandemic, which has been associated with a spike in alcohol abuse, and a subsequent increase in hospitalization rates for ALD. A key knowledge gap that underlies the lack of novel therapies for ALD is a need to better understand the pathogenic mechanisms that contribute to ALD initiation, particularly with respect to hepatic lipid accumulation and the development of fatty liver, which is the first step in the ALD spectrum. The goal of this review is to evaluate the existing literature to gain insight into the pathogenesis of alcohol-associated fatty liver, and to synthesize alcohol’s known effects on hepatic lipid metabolism. To achieve this goal, we specifically focus on studies from transgenic mouse models of ALD, allowing for a genetic dissection of alcohol’s effects, and integrate these findings with our current understanding of ALD pathogenesis. Existing studies using transgenic mouse models of ALD have revealed roles for specific genes involved in hepatic lipid metabolic pathways including fatty acid uptake, mitochondrial β-oxidation, de novo lipogenesis, triglyceride metabolism, and lipid droplet formation. In addition to reviewing this literature, we conclude by identifying current gaps in our understanding of how alcohol abuse impairs hepatic lipid metabolism and identify future directions to address these gaps. In summary, transgenic mice provide a powerful tool to understand alcohol’s effect on hepatic lipid metabolism and highlight that alcohol abuse has diverse effects that contribute to the development of alcohol-associated fatty liver disease.
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Torres S, Segalés P, García-Ruiz C, Fernández-Checa JC. Mitochondria and the NLRP3 Inflammasome in Alcoholic and Nonalcoholic Steatohepatitis. Cells 2022; 11:1475. [PMID: 35563780 PMCID: PMC9105698 DOI: 10.3390/cells11091475] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2022] [Revised: 04/18/2022] [Accepted: 04/25/2022] [Indexed: 12/12/2022] Open
Abstract
Alcoholic (ASH) and nonalcoholic steatohepatitis (NASH) are advanced stages of fatty liver disease and two of the most prevalent forms of chronic liver disease. ASH and NASH are associated with significant risk of further progression to cirrhosis and hepatocellular carcinoma (HCC), the most common type of liver cancer, and a major cause of cancer-related mortality. Despite extensive research and progress in the last decades to elucidate the mechanisms of the development of ASH and NASH, the pathogenesis of both diseases is still poorly understood. Mitochondrial damage and activation of inflammasome complexes have a role in inducing and sustaining liver damage. Mitochondrial dysfunction produces inflammatory factors that activate the inflammasome complexes. NLRP3 inflammasome (nucleotide-binding oligomerization domain-like receptor protein 3) is a multiprotein complex that activates caspase 1 and the release of pro-inflammatory cytokines, including interleukin-1β (IL-1β) and interleukin-18 (IL-18), and contributes to inflammatory pyroptotic cell death. The present review, which is part of the issue "Mitochondria in Liver Pathobiology", provides an overview of the role of mitochondrial dysfunction and NLRP3 activation in ASH and NASH.
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Affiliation(s)
- Sandra Torres
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Paula Segalés
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
| | - Carmen García-Ruiz
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - José C. Fernández-Checa
- Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), 08036 Barcelona, Spain; (S.T.); (P.S.)
- Liver Unit, Hospital Clinic I Provincial de Barcelona, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
- Center for the Study of Liver and Gastrointestinal Diseases (CIBERehd), Carlos III National Institute of Health, 28029 Madrid, Spain
- Division of Gastrointestinal and Liver Diseases, Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
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