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Yang YJ, Kim MJ, Yang JH, Heo JW, Kim HH, Kim WH, Kim GS, Lee HJ, Kim YW, Kim KY, Park KI. Liquid Chromatography/Tandem Mass Spectrometry Analysis of Sophora flavescens Aiton and Protective Effects against Alcohol-Induced Liver Injury and Oxidative Stress in Mice. Antioxidants (Basel) 2024; 13:541. [PMID: 38790646 PMCID: PMC11117756 DOI: 10.3390/antiox13050541] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 04/26/2024] [Accepted: 04/26/2024] [Indexed: 05/26/2024] Open
Abstract
In this study, we investigated the hepatoprotective effects of an ethanol extract of Sophora flavescens Aiton (ESF) on an alcohol-induced liver disease mouse model. Alcoholic liver disease (ALD) was caused by the administration of ethanol to male C57/BL6 mice who were given a Lieber-DeCarli liquid diet, including ethanol. The alcoholic fatty liver disease mice were orally administered ESF (100 and 200 mg/kg bw/day) or silymarin (50 mg/kg bw/day), which served as a positive control every day for 16 days. The findings suggest that ESF enhances hepatoprotective benefits by significantly decreasing serum levels of aspartate transaminase (AST) and alanine transaminase (ALT), markers for liver injury. Furthermore, ESF alleviated the accumulation of triglyceride (TG) and total cholesterol (TC), increased serum levels of superoxide dismutase (SOD) and glutathione (GSH), and improved serum alcohol dehydrogenase (ADH) activity in the alcoholic fatty liver disease mice model. Cells and organisms rely on the Kelch-like ECH-associated protein 1- Nuclear factor erythroid 2-related factor 2 (Keap1-Nrf2) system as a critical defensive mechanism in response to oxidative stress. Therefore, Nrf2 plays an important role in ALD antioxidant responses, and its level is decreased by increased reactive oxidation stress (ROS) in the liver. ESF increased Nrf2, which was decreased in ethanol-damaged livers. Additionally, four polyphenol compounds were identified through a qualitative analysis of the ESF using LC-MS/MS. This study confirmed ESF's antioxidative and hangover-elimination effects and suggested the possibility of using Sophora flavescens Aiton (SF) to treat ALD.
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Affiliation(s)
- Ye Jin Yang
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
| | - Min Jung Kim
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
| | - Ju-Hye Yang
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea;
| | - Ji Woong Heo
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
| | - Hun Hwan Kim
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
| | - Woo H. Kim
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
| | - Gon Sup Kim
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
| | - Hu-Jang Lee
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
| | - Young Woo Kim
- School of Korean Medicine, Dongguk University, Gyeongju 38066, Republic of Korea;
| | - Kwang Youn Kim
- Korean Medicine (KM) Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Republic of Korea;
| | - Kwang Il Park
- Departments of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea; (Y.J.Y.); (M.J.K.); (J.W.H.); (H.H.K.); (W.H.K.); (G.S.K.); (H.-J.L.)
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Dos Santos AC, França TCS, Venzon L, Polli V, Polleti G, Trembulak E, Pilati SFM, da Silva LM. Are silymarin and N-acetylcysteine able to prevent liver damage mediated by multiple factors? Findings against ethanol plus LPS-induced liver injury in mice. J Biochem Mol Toxicol 2024; 38:e23560. [PMID: 37860953 DOI: 10.1002/jbt.23560] [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: 04/20/2023] [Revised: 09/11/2023] [Accepted: 10/05/2023] [Indexed: 10/21/2023]
Abstract
This study investigated the effect of N-acetylcysteine (NAC) and silymarin (SIL) in the liver of mice exposed to ethanol and lipopolysaccharides (LPS). Mice were divided into four groups (n = 6): naive, vehicle, NAC (200 mg/kg), and SIL (200 mg/kg). Treatments were given orally (po) once daily for 10 days. Liver injury was induced by administration of ethanol (30%, po) for 10 days, once daily, followed by a single administration of LPS (2 mg/kg, ip) 24 h before euthanasia. After the treatment period, animals were euthanized, and liver and blood samples were collected. NAC, but not SIL, prevented the increase in oxalacetic glutamic transaminase (OGT) and pyruvic glutamic transaminase (PGT) serum levels. NAC and SIL did not restore levels of reduced glutathione or hepatic malonaldehyde. The treatments with NAC or SIL showed no difference in the activity of glutathione S-transferase, superoxide dismutase, and catalase compared to vehicle group. Myeloperoxidase and N-acetylglucosaminidase activities are increased, as well as the IL-6 and IL-10 levels in the liver. The treatment with NAC, but not SIL, reduced the N-acetylglucosamines activity and the IL-6 and IL-10 amount in the liver. Histological findings revealed microsteatosis in the vehicle group, which was not prevented by SIL but was partially reduced in animals receiving NAC. Unlike other liver injury models, NAC (200 mg/kg) or SIL (200 mg/kg) did not positively affect antioxidant patterns in liver tissue of animals exposed to ethanol plus LPS, but NAC treatment displays anti-inflammatory properties in this model.
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Affiliation(s)
- Ana Caroline Dos Santos
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | - Larissa Venzon
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Vitor Polli
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Gustavo Polleti
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | - Erica Trembulak
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
| | | | - Luísa Mota da Silva
- Postgraduate Program in Pharmaceutical Sciences, Universidade do Vale do Itajaí, Itajaí, Santa Catarina, Brazil
- LaFaTI-Laboratório de Farmacologia do Trato Gastrointestinal e suas Interações, Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, Brazil
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Zhou S, Zhong H, Wang Y, Wang X, Pan H, Liu X, Hu L. JNK/MAPK pathway regulation by BEX2 gene silencing in alcoholic hepatitis mice: Effects on oxidative stress. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2023; 47:1869-1882. [PMID: 37864534 DOI: 10.1111/acer.15178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 08/11/2023] [Accepted: 08/18/2023] [Indexed: 10/23/2023]
Abstract
BACKGROUND Alcoholic hepatitis (AH) is a severe alcoholic-related liver disease that is a leading cause of morbidity and mortality, for which effective treatments are lacking. Brain-expressed X-linked gene 2 (BEX2) has been implicated in various diseases, but its association with AH has received limited attention. Thus, this study investigated BEX2's impact on the progression of AH by affecting the c-Jun NH2-terminal kinase/mitogen-activated protein kinase (JNK/MAPK) pathway. METHODS Microarray dataset GSE28619 from the Gene Expression Omnibus database was used to identify differentially expressed genes in AH. Immunohistochemistry, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL), Western blot analysis, and flow cytometry were used to measure various factors in the liver tissue of AH mice. RESULTS BEX2 expression was significantly upregulated in the model. BEX2 gene silencing increased the levels of glutathione peroxidase and superoxide dismutase while decreasing malondialdehyde content; phosphorylation of JNK, c-JUN, and p38MAPK; apoptosis rate; and the extent of JNK/MAPK pathway activation. CONCLUSIONS These findings provide valuable insights into the mechanisms underlying AH development and highlight the potential role of BEX2 gene expression as a promising therapeutic target for AH.
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Affiliation(s)
- Shuai Zhou
- Department of General Surgery, Anhui No. 2 Provincial People's Hospital, Anhui Medical University, Hefei, China
| | - Hai Zhong
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Yong Wang
- Department of General Surgery, Anhui No. 2 Provincial People's Hospital, Anhui Medical University, Hefei, China
| | - Xiaoguang Wang
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Hongtao Pan
- Department of General Surgery, Anhui No. 2 Provincial People's Hospital, Anhui Medical University, Hefei, China
| | - Xiaolin Liu
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
| | - Lingyu Hu
- Department of Surgery, The Second Affiliated Hospital of Jiaxing University, Jiaxing, China
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Cancino J, Lazo S, Fonseca D. [Stomatological management of patients with liver disease: a review of the literature]. REVISTA CIENTÍFICA ODONTOLÓGICA 2023; 11:e153. [PMID: 38288454 PMCID: PMC10809970 DOI: 10.21142/2523-2754-1102-2023-153] [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: 02/16/2023] [Accepted: 05/28/2023] [Indexed: 01/31/2024] Open
Abstract
Introduction The liver is the organ responsible for the metabolism of nutrients, some drugs, and the production of coagulation factors. According to the World Health Organization, approximately 23 million people worldwide are diagnosed with liver disease each year. As a result, it is common for dentists to encounter these patients on a daily basis in their practice. The objective of this review is to establish the dental management of patients with liver disease. Material and methods A manual literature search was conducted using the indexed articles in PUBMED and EBSCO databases using the keywords "oral surgery," AND "liver disease," AND "hepatic cirrhosis," AND "dental management". Results Patients with liver disease present important characteristics for the dentist, which must be recognized in order to perform procedures with the lowest risk of intraoperative and postoperative complications. A patient with poorly controlled underlying liver disease is more prone to infections and bleeding, which implies a high risk of morbidity. Conclusions Dental care for patients with liver disease should be assessed according to the reason for consultation, control of the disease, the complexity of the procedure to be performed, and both intraoperative and postoperative hemostatic measures. All necessary hemostatic measures should be considered and dose adjustments should be considered in the use of NSAIDs.
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Affiliation(s)
- Javiera Cancino
- Facultad de Odontología, Universidad Finis Terrae. Santiago, Chile. Universidad Finis Terrae Facultad de Odontología Universidad Finis Terrae Santiago Chile
| | - Sebastián Lazo
- Facultad de Odontología, Universidad Finis Terrae. Santiago, Chile. Universidad Finis Terrae Facultad de Odontología Universidad Finis Terrae Santiago Chile
| | - Diego Fonseca
- Facultad de Odontología, Universidad del Desarrollo. Santiago, Chile. Universidad del Desarrollo Facultad de Odontología Universidad del Desarrollo Santiago Chile
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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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Gupta H, Kim SH, Kim SK, Han SH, Kwon HC, Suk KT. Beneficial Shifts in Gut Microbiota by Lacticaseibacillus rhamnosus R0011 and Lactobacillus helveticus R0052 in Alcoholic Hepatitis. Microorganisms 2022; 10:microorganisms10071474. [PMID: 35889193 PMCID: PMC9319967 DOI: 10.3390/microorganisms10071474] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Revised: 07/18/2022] [Accepted: 07/18/2022] [Indexed: 02/01/2023] Open
Abstract
Gut microbiota performs indispensable functions in the pathophysiology of alcoholic hepatitis (AH). We investigated the effects of Lacticaseibacillus rhamnosus R0011 and Lactobacillus helveticus for gut microbial restoration toward eubiosis in patients with AH. A multicenter, double-blind, and randomized trial was conducted. Probiotics (n = 44) and placebo (n = 45) groups received, during 7 days, L. rhamnosus R0011/L. helveticus R0052 at 120 mg/day and placebo. All patients were hospitalized to ensure abstinence. Liver function, lipopolysaccharide level, and stool analysis were evaluated in patients before and after 7 days of treatment. At baseline, the dominant bacteria were Gram-negative in both groups which decreased after the probiotics treatment and exhibited a significant reduction in lipopolysaccharide level (p < 0.001). The probiotics ameliorated the Child−Pugh scores (p < 0.001). Furthermore, the probiotics group showed a decline in the levels of alanine aminotransferase and gamma-glutamyltranspeptidase (p < 0.05). The probiotics changed the gut microbial composition at various taxonomical levels. The proportion of Bacteroidetes (147%) was increased after 7 days of probiotics supplementation while Proteobacteria (30%) and Fusobacteria (0%) were decreased. Administration of L. rhamnosus R0011 and L. helveticus R0052 conceivably associated with restoration of gut microbiome in AH patients and improved AH by modulating the gut−liver axis.
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Affiliation(s)
- Haripriya Gupta
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea; (H.G.); (S.K.K.)
| | - Sung Hun Kim
- Korea Institute of Science and Technology, Gangneung 25451, Korea;
| | - Seul Ki Kim
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea; (H.G.); (S.K.K.)
| | - Sang Hak Han
- Department of Pathology, Hallym University College of Medicine, Chuncheon 24252, Korea;
| | - Hak Cheol Kwon
- Korea Institute of Science and Technology, Gangneung 25451, Korea;
- Correspondence: (H.C.K.); (K.T.S.)
| | - Ki Tae Suk
- Institute for Liver and Digestive Diseases, Hallym University, Chuncheon 24252, Korea; (H.G.); (S.K.K.)
- Correspondence: (H.C.K.); (K.T.S.)
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Madathanapalli A, Tang Q, Lammert C, Samala N, Shah VH, Sanyal A, Chalasani N, Desai A. Health-related quality of life is dynamic in alcoholic hepatitis and responds to improvement in liver disease and reduced alcohol consumption. Alcohol Clin Exp Res 2022; 46:252-261. [PMID: 34862610 PMCID: PMC8858853 DOI: 10.1111/acer.14756] [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: 05/10/2021] [Revised: 11/17/2021] [Accepted: 11/23/2021] [Indexed: 02/03/2023]
Abstract
BACKGROUND The impact of alcoholic hepatitis (AH) on health-related quality of life (HRQOL) remains inadequately described. We aimed to characterize HRQOL in AH and heavy drinkers (HD), and its associations with clinical variables and outcomes. METHODS This is a post hoc analysis of participants in the Translational Research and Evolving Alcoholic Hepatitis Treatment 001 study (NCT02172898). HRQOL was measured using Short Form Health Survey (SF-36). Mean SF-36 scores were compared in AH and HD with two-sample t-tests. Associations among clinical characteristics, 30-day mortality, and SF-36 mental and physical component scores (MC, PC) were investigated with generalized linear and logistic multivariate regression models. Trends of MC and PC scores were analyzed using one-way ANOVA. RESULTS Participants with AH (n = 258) and HD (n = 181) were similar demographically. AH cases had a mean Model for End-stage Liver Disease (MELD) score of 23 (7). AH cases had lower PC scores [37 (10) vs. 48 (11), p < 0.001] but higher MC scores [37 (13) vs. 32 (13), p < 0.001]. MC scores were independently associated with age, male gender, and daily alcohol consumption; PC scores were independently associated with age, BMI, alanine aminotransferase concentration, alkaline phosphatase concentration, white blood cell counts, and the presence of ascites. With each 5-point decrease in the baseline PC score, the adjusted odds of dying within 30 days increased by 26.7% (95% CI 1% to 46%). Over time, HRQOL in AH improved (day 0 to day 180 delta PC score: 4.5 ± 1.7, p = 0.008; delta MC score: 9.8 ± 2.0, p < 0.001). Participants with a MELD score <15 by day 180 had greater increases in PC scores than those with MELD score ≥15 (delta PC score 7.1 ± 1.8 vs. -0.7 ± 2.3, p = 0.009), while those abstinent by day 180 had greater increases in MC scores than those who were not abstinent (delta MC score 9.1 ± 1.8 vs. 2.8 ± 2.4, p = 0.044). CONCLUSIONS HRQOL is poor in AH and HD in a domain-specific pattern. Independent of MELD score, lower baseline HRQOL is associated with higher 30-day mortality. Over time, HRQOL improves with greater gains seen in individuals with improved MELD scores and those who were abstinent.
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Affiliation(s)
| | - Qing Tang
- Department of Biostatistics and Health Data Science, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Craig Lammert
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
| | - Niharika Samala
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester MN, USA
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, VCU School of Medicine, Richmond VA, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
| | - Archita Desai
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis IN, USA
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Crosstalk between Oxidative Stress and Inflammatory Liver Injury in the Pathogenesis of Alcoholic Liver Disease. Int J Mol Sci 2022; 23:ijms23020774. [PMID: 35054960 PMCID: PMC8775426 DOI: 10.3390/ijms23020774] [Citation(s) in RCA: 105] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is characterized by the injury, inflammation, and scarring in the liver owing to excessive alcohol consumption. Currently, ALD is a leading cause for liver transplantation. Therefore, extensive studies (in vitro, in experimental ALD models and in humans) are needed to elucidate pathological features and pathogenic mechanisms underlying ALD. Notably, oxidative changes in the liver have been recognized as a signature trait of ALD. Progression of ALD is linked to the generation of highly reactive free radicals by reactions involving ethanol and its metabolites. Furthermore, hepatic oxidative stress promotes tissue injury and, in turn, stimulates inflammatory responses in the liver, forming a pathological loop that promotes the progression of ALD. Accordingly, accumulating further knowledge on the relationship between oxidative stress and inflammation may help establish a viable therapeutic approach for treating ALD.
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Yang Z, Zhang T, Kusumanchi P, Tang Q, Sun Z, Radaeva S, Peiffer B, Shah VH, Kamath P, Gores GJ, Sanyal A, Chalasani N, Jiang Y, Huda N, Ma J, Liangpunsakul S. Transcriptomic Analysis Reveals the MicroRNAs Responsible for Liver Regeneration Associated With Mortality in Alcohol-Associated Hepatitis. Hepatology 2021; 74:2436-2451. [PMID: 34096637 PMCID: PMC8542623 DOI: 10.1002/hep.31994] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 05/03/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS We conducted a comprehensive serum transcriptomic analysis to explore the roles of microRNAs (miRNAs) in alcohol-associated hepatitis (AH) pathogenesis and their prognostic significance. APPROACH AND RESULTS Serum miRNA profiling was performed in 15 controls, 20 heavy drinkers without liver disease, and 65 patients with AH and compared to publicly available hepatic miRNA profiling in AH patients. Among the top 26 miRNAs, expression of miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p were significantly reduced in both serum and liver of AH patients. Pathway analysis of the potential targets of these miRNAs uncovered the genes related to DNA synthesis and cell-cycle progression pathways, including ribonucleotide reductase regulatory subunit M2 (RRM2), cyclin D1 (CCND1), cyclin D2 (CCND2), MYC proto-oncogene (MYC), and phorbol-12-myristate-13-acetate-induced protein 1 (PMAIP1). We found a significant increase in the protein expression of RRM2, CCND1, and CCND2, but not MYC and PMAIP1, in AH patients who underwent liver transplantation; miR-26b-5p and miR-30b-5p inhibited the 3'-UTR (untranslated region) luciferase activity of RRM2 and CCND2, and miR-20a-5p reduced the 3'-UTR luciferase activity of CCND1 and CCND2. During a median follow-up of 346 days, 21% of AH patients died; these patients had higher body mass index (BMI), Model for End-Stage Liver Disease (MELD), and serum miR-30b-5p, miR-20a-5p, miR-146a-5p, and miR-26b-5p than those who survived. Cox regression analysis showed that BMI, MELD score, miR-20a-5p, miR-146a-5p, and miR-26b-5p predicted mortality. CONCLUSIONS Patients with AH attempt to deal with hepatocyte injury by down-regulating specific miRNAs and up-regulating genes responsible for DNA synthesis and cell-cycle progression. Higher expression of these miRNAs, suggestive of a diminished capacity in liver regeneration, predicts short-term mortality in AH patients.
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Affiliation(s)
- Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Qing Tang
- Department of Biostatistics, Indiana University, Indianapolis, IN
| | - Zhaoli Sun
- Department of Surgery, John Hopkins University, Rockville, MD
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, Rockville, MD
| | - Brandon Peiffer
- Department of Surgery, John Hopkins University, Rockville, MD
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Patrick Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Greg J. Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Virginia Commonwealth University, Richmond, VA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Nazmul Huda
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
- Roudebush Veterans Administration Medical Center, Indianapolis, IN
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
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Shamseddeen H, Madathanapalli A, Are VS, Shah VH, Sanyal AJ, Tang Q, Liang T, Gelow K, Zimmers TA, Chalasani N, Desai AP. Changes in Serum Myostatin Levels in Alcoholic Hepatitis Correlate with Improvement in MELD. Dig Dis Sci 2021; 66:3062-3073. [PMID: 33074470 PMCID: PMC8053725 DOI: 10.1007/s10620-020-06632-5] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/20/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Alcoholic hepatitis (AH) is a serious clinical syndrome often associated with muscle wasting. Myostatin, a member of the transforming growth factor-β superfamily, has been studied in diseases with muscle wasting; however, the role of myostatin in AH is unknown. AIMS To investigate the association between myostatin, clinical variables, and outcomes in AH. METHODS We analyzed data for cases of AH and controls of heavy drinkers (HD) in TREAT001 (NCT02172898) with serum myostatin levels (AH: n = 131, HD: n = 124). We compared characteristics between the two groups at baseline, 30, and 90 days and explored correlations between myostatin and clinical variables. We then modeled the relationship of myostatin to other variables, including mortality. RESULTS Baseline median myostatin was lower in AH compared to HD (males: 1.58 vs 3.06 ng/ml, p < 0.001; females: 0.84 vs 2.01 ng/ml, p < 0.001). In multivariable linear regression, bilirubin, WBC, and platelet count remained negatively correlated with myostatin in AH. AH females who died at 90 days had significantly lower myostatin, but in a multivariable logistic model with MELD and myostatin, only MELD remained significantly associated with 90-day mortality. During 1-year follow-up, AH cases (n = 30) demonstrated an increase in myostatin (mean, 1.73 ng/ml) which correlated with decreasing MELD scores (ρ = - 0.42, p = 0.01). CONCLUSIONS Myostatin levels are significantly lower in AH compared to HD and are negatively correlated with total bilirubin, WBC, and platelet count. Myostatin increased as patients experienced decreases in MELD. Overall, myostatin demonstrated a dynamic relationship with AH outcomes and future studies are needed to understand the prognostic role of myostatin in AH.
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Affiliation(s)
- Hani Shamseddeen
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | | | - Vijay S Are
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Arun J Sanyal
- Division of Gastroenterology and Hepatology, VCU School of Medicine, Richmond, VA, USA
| | - Qing Tang
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Tiebing Liang
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Kayla Gelow
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Teresa A Zimmers
- Surgical Oncology, Surgery-Chairman's Office, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA
| | - Archita P Desai
- Division of Gastroenterology and Hepatology, Indiana University School of Medicine, 702 Rotary Circle, Suite 225, Indianapolis, IN, 46202, USA.
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11
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Han S, Yang Z, Zhang T, Ma J, Chandler K, Liangpunsakul S. Epidemiology of Alcohol-Associated Liver Disease. Clin Liver Dis 2021; 25:483-492. [PMID: 34229835 PMCID: PMC8996817 DOI: 10.1016/j.cld.2021.03.009] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Alcohol-associated liver disease (ALD) is a consequence of excessive alcohol use. It comprises a spectrum of histopathologic changes ranging from simple steatosis, steatohepatitis, and cirrhosis to hepatocellular carcinoma. The public health impact of ALD is growing because of an increase in the prevalence and incidence of ALD in parallel with liver transplant and mortalities. There are multiple factors involved in the pathogenesis and progression of ALD. Reducing alcohol consumption is the cornerstone of ALD management. The efforts to reduce excessive alcohol use at the individual and population levels are urgently needed to prevent adverse outcomes from ALD.
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Affiliation(s)
- Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA,Key Laboratory of Carcinogenesis and Translational Research, Peking University Cancer Hospital, Beijing, China
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA
| | - Jing Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA
| | - Kristina Chandler
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202, USA,Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA,Roudebush Veterans Administration Medical Center, Indianapolis, IN, USA,Corresponding author. Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, 702 Rotary Circle, Indianapolis, IN 46202.
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12
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Serum Acylcarnitines Associated with High Short-Term Mortality in Patients with Alcoholic Hepatitis. Biomolecules 2021; 11:biom11020281. [PMID: 33672832 PMCID: PMC7917657 DOI: 10.3390/biom11020281] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 02/10/2021] [Indexed: 01/11/2023] Open
Abstract
Alcohol-related liver disease is one of the most prevalent liver diseases in the United States. Early stages of alcohol-related liver disease are characterized by accumulation of triglycerides in hepatocytes. Alcoholic hepatitis is a severe form of alcohol-related liver disease associated with significant morbidity and mortality. We sought to identify patients who are at greatest risk of death using serum lipids. First, we performed lipidomics analysis on serum samples collected from 118 patients with alcoholic hepatitis to identify lipid markers that are associated with high risk of death. Next, we performed gene set enrichment analysis on liver transcriptomics data to identify dysregulated lipid metabolism in patients who received liver transplantation. Finally, we built a random forest model to predict 30-day mortality using serum lipids. A total of 277 lipids were annotated in the serum of patients with alcoholic hepatitis, among which 25 were significantly different between patients in the deceased and alive groups. Five chemical clusters were significantly altered between the two groups. In particular, acylcarnitine cluster was enriched in the deceased group. Several hepatic lipid metabolism pathways were dysregulated in patients with alcoholic hepatitis who received liver transplantation. The mRNA expression of genes involved in the fatty acid transport into mitochondria and β-oxidation were also dysregulated. When predicting 30-day mortality in alcoholic hepatitis patients using serum lipids, we found that the area under the curve achieved 0.95. Serum lipids such as acylcarnitines may serve as biomarkers to identify alcoholic hepatitis patients at the greatest risk of death.
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13
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MORPHOLOGICAL AND FUNCTIONAL CHANGES OF THE HEPATIC VASCULAR BED UNDER THE CONDITIONS OF MODELING ALCOHOLIC HEPATITIS. WORLD OF MEDICINE AND BIOLOGY 2021. [DOI: 10.26724/2079-8334-2021-3-77-229-236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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14
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Viral Hepatitis and Iron Dysregulation: Molecular Pathways and the Role of Lactoferrin. Molecules 2020; 25:molecules25081997. [PMID: 32344579 PMCID: PMC7221917 DOI: 10.3390/molecules25081997] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 04/16/2020] [Accepted: 04/23/2020] [Indexed: 02/06/2023] Open
Abstract
The liver is a frontline immune site specifically designed to check and detect potential pathogens from the bloodstream to maintain a general state of immune hyporesponsiveness. One of the main functions of the liver is the regulation of iron homeostasis. The liver detects changes in systemic iron requirements and can regulate its concentration. Pathological states lead to the dysregulation of iron homeostasis which, in turn, can promote infectious and inflammatory processes. In this context, hepatic viruses deviate hepatocytes' iron metabolism in order to better replicate. Indeed, some viruses are able to alter the expression of iron-related proteins or exploit host receptors to enter inside host cells. Lactoferrin (Lf), a multifunctional iron-binding glycoprotein belonging to the innate immunity, is endowed with potent antiviral activity, mainly related to its ability to block viral entry into host cells by interacting with viral and/or cell surface receptors. Moreover, Lf can act as an iron scavenger by both direct iron-chelation or the modulation of the main iron-related proteins. In this review, the complex interplay between viral hepatitis, iron homeostasis, and inflammation as well as the role of Lf are outlined.
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15
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Xia Y, Yang J, Sanyal AJ, Shah VH, Chalasani NP, Yu Q, Zheng X, Li W. Persistent Hyperactivation of Endothelial Cells in Patients with Alcoholic Hepatitis. Alcohol Clin Exp Res 2020; 44:1075-1087. [PMID: 32246771 DOI: 10.1111/acer.14331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Accepted: 03/19/2020] [Indexed: 12/12/2022]
Abstract
BACKGROUND Alcoholic hepatitis (AH) is a severe inflammatory liver disease that develops in some heavy drinkers. AH patients have intense hepatic infiltration of leukocytes. Up-regulation of cell adhesion molecules (CAMs) upon endothelial cell (EC) activation plays an important role in leukocyte transendothelial migration. CAMs can shed from EC surface and accumulate in the blood, serving as soluble markers for EC activation. In this study, we examined the impact of heavy drinking on expression of soluble forms of EC activation markers (CD146, ICAM-1, VCAM-1, and VEGF-A) and the effect of alcohol abstinence on the reversal of these abnormalities in heavy drinkers with and without AH. METHODS ELISA and multiplex immunoassays were used to measure soluble EC activation markers in plasma samples from 79 AH patients, 66 heavy drinkers without overt liver disease (HDC), and 44 healthy controls (HC) at baseline, 31 AH patients and 30 HDC at 6-month follow-up, and 18 AH patients and 25 HDC at 12-month follow-up. RESULTS At baseline, the 4 soluble markers were significantly up-regulated in AH patients compared with HDC and HC, whereas only sVCAM-1 was elevated in HDC relative to HC. At follow-ups, plasma levels of CD146, VCAM-1, and VEGF-A remained higher in AH patients, even for those who stopped drinking. These dysregulated markers correlated with AH disease severity, clinical parameters, and several soluble inflammatory factors. CONCLUSIONS The levels of soluble CD146, ICAM-1, VCAM-1, and VEGF-A were highly elevated in AH patients, and alcohol abstinence did not completely reverse these abnormalities.
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Affiliation(s)
- Ying Xia
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Jing Yang
- School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.,Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Arun J Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Naga P Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Xiaoqun Zheng
- Department of Clinical Laboratory, the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.,School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana
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16
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Jiang Y, Zhang T, Kusumanchi P, Han S, Yang Z, Liangpunsakul S. Alcohol Metabolizing Enzymes, Microsomal Ethanol Oxidizing System, Cytochrome P450 2E1, Catalase, and Aldehyde Dehydrogenase in Alcohol-Associated Liver Disease. Biomedicines 2020; 8:50. [PMID: 32143280 PMCID: PMC7148483 DOI: 10.3390/biomedicines8030050] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 02/20/2020] [Accepted: 02/29/2020] [Indexed: 12/12/2022] Open
Abstract
Once ingested, most of the alcohol is metabolized in the liver by alcohol dehydrogenase to acetaldehyde. Two additional pathways of acetaldehyde generation are by microsomal ethanol oxidizing system (cytochrome P450 2E1) and catalase. Acetaldehyde can form adducts which can interfere with cellular function, leading to alcohol-induced liver injury. The variants of alcohol metabolizing genes encode enzymes with varied kinetic properties and result in the different rate of alcohol elimination and acetaldehyde generation. Allelic variants of these genes with higher enzymatic activity are believed to be able to modify susceptibility to alcohol-induced liver injury; however, the human studies on the association of these variants and alcohol-associated liver disease are inconclusive. In addition to acetaldehyde, the shift in the redox state during alcohol elimination may also link to other pathways resulting in activation of downstream signaling leading to liver injury.
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Affiliation(s)
- Yanchao Jiang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Ting Zhang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Praveen Kusumanchi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Sen Han
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Zhihong Yang
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA; (Y.J.); (T.Z.); (P.K.); (S.H.)
- Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202, USA
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17
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Qian WH, Liu YY, Li X, Pan Y. MicroRNA-141 ameliorates alcoholic hepatitis‑induced intestinal injury and intestinal endotoxemia partially via a TLR4-dependent mechanism. Int J Mol Med 2019; 44:569-581. [PMID: 31173169 PMCID: PMC6605973 DOI: 10.3892/ijmm.2019.4221] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Accepted: 04/23/2019] [Indexed: 12/20/2022] Open
Abstract
Alcoholic hepatitis (AH) is a fatal inflammatory syndrome with no effective treatments. Intestinal injury and intestinal endotoxemia (IETM) contribute greatly in the development of AH. MicroRNAs (miRNAs/miRs) have been reported to affect intestinal injury. The present study aims to investigate the role of miR-141 in intestinal injury and IETM of AH. An AH model was successfully established in mice and they were the injected with a series of miR-141 mimic, miR-141 inhibitor or toll like receptor 4 monoclonal antibody (TLR4mAb; an inhibitor of the Toll-like receptor TLR pathway). After that, the intestinal tissues and intestinal epithelial cells were isolated from differently treated AH mice. The expression of miR-141 and TLR pathway-associated genes and the levels of inflammatory factors were determined. Furthermore, a target prediction program and a luciferase reporter assay were employed to examine whether miR-141 targets TLR4. Finally, MTT and transwell assays were carried out to detect cell viability and cell permeability. Intestinal tissues from AH mice treated with miR-141 mimic or TLR4mAb exhibited lower levels of inflammatory factors and reduced expression of the TLR pathway-associated genes, suggesting a decreased inflammatory response as well as inactivation of the TLR pathway by miR-141. The luciferase reporter assay suggested that miR-141 negatively regulated TLR4. Intestinal epithelial cells treated with miR-141 mimic or TLR4mAb demonstrated enhanced viability and reduced permeability. Opposite results were observed in AH mice treated with a miR-141 inhibitor. Collectively, the results of the present study demonstrated that miR-141 could ameliorate intestinal injury and repress the progression of IETM through targeting TLR4 and inhibiting the TLR pathway.
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Affiliation(s)
- Wei-He Qian
- Department of Clinical Laboratory, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu 223302, P.R. China
| | - Yuan-Yuan Liu
- Department of Endocrinology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Xiang Li
- Department of Clinical Laboratory, The Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an, Jiangsu 223302, P.R. China
| | - Yan Pan
- Department of Clinical Laboratory, Lianshui County People's Hospital, Huai'an, Jiangsu 223400, P.R. China
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18
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Li W, Lin EL, Liangpunsakul S, Lan J, Chalasani S, Rane S, Puri P, Kamath PS, Sanyal AJ, Shah VH, Radaeva S, Crabb DW, Chalasani N, Yu Q. Alcohol Abstinence Does Not Fully Reverse Abnormalities of Mucosal-Associated Invariant T Cells in the Blood of Patients With Alcoholic Hepatitis. Clin Transl Gastroenterol 2019; 10:e00052. [PMID: 31211759 PMCID: PMC6613857 DOI: 10.14309/ctg.0000000000000052] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 02/22/2019] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities.
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Affiliation(s)
- Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Edward L. Lin
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Roudebush Veterans Administration Medical Center, Indianapolis, Indiana, USA
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Jie Lan
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Sai Chalasani
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Sushmita Rane
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Puneet Puri
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Arun J. Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland, USA
| | - David W. Crabb
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
- Internal Medicine, Eskenazi Health, Indianapolis, Indiana, USA
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana, USA
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19
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Feng R, Chen JH, Liu CH, Xia FB, Xiao Z, Zhang X, Wan JB. A combination of Pueraria lobata and Silybum marianum protects against alcoholic liver disease in mice. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2019; 58:152824. [PMID: 30836218 DOI: 10.1016/j.phymed.2019.152824] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 01/03/2019] [Accepted: 01/08/2019] [Indexed: 05/19/2023]
Abstract
BACKGROUND Excess alcohol exposure leads to alcoholic liver disease (ALD). Pueraria lobata (PUE) and Silybum marianum (SIL) are two well-known hepatoprotective herbal remedies with various activities. The possible effect of combination of PUE and SIL on ALD has not been elucidated yet. PURPOSE We aimed to demonstrate that the combination of PUE and SIL prevents against alcoholic liver injury in mice using a model of chronic-plus-single-binge ethanol feeding. STUDY DESIGN Male C57BL/6 mice were randomly divided into five groups (n = 8-10), namely the control group (CON), ethanol-induced liver injury group (ETH), 150 mg/kg PUE treated group (PUE), 60 mg/kg SIL treated group (SIL), 210 mg/kg PUE+SIL treatment group (PUE+SIL). Except control group, all animals were fed a modified Lieber-DeCarli ethanol liquid diet for 10 days. While, control group received Lieber-DeCarli control diet containing isocaloric maltose dextrin substituted for ethanol. On day 11, the mice orally received a single dose of 31.5% (v/v) ethanol (5 g/kg BW) or an isocaloric maltose solution. RESULTS Ethanol exposure caused liver injury, as demonstrated by remarkably increased plasma parameters, histopathological changes, the increased lipid accumulation, oxidative stress and inflammation in liver. These alterations were ameliorated by the treatments of PUE, SIL and PUE+SIL. While, the PUE+SIL treatment showed the most effective protection, which was associated with reducing alcohol-induced hepatic steatosis via upregulating LKB1/AMPK/ACC signaling, and inhibiting hepatic inflammation via LPS-triggered TLR4-mediated NF-κB signaling pathway. Our results also indicated that the hepatoprotective effects of SIL+PUE might mainly attribute to the protection of SIL and PUE alone in alcohol-induced hepatic steatosis and hepatic inflammation, respectively. CONCLUSION These findings also suggest that the combination of PUE and SIL has a potential to be developed as a functional food for the management of ALD.
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Affiliation(s)
- Ruibing Feng
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
| | - Jie-Hua Chen
- Nutrition and Health Research Centre, By-Health Co. LTD, Guangzhou, China
| | - Cong-Hui Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
| | - Fang-Bo Xia
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China
| | - Zeyu Xiao
- Translational Medicine Collaborative Innovation Center, Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xuguang Zhang
- Nutrition and Health Research Centre, By-Health Co. LTD, Guangzhou, China.
| | - Jian-Bo Wan
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Taipa, Macao, China.
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20
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Abstract
Excessive alcohol consumption can lead to a spectrum of liver histopathology, including steatosis, steatohepatitis, foamy degeneration, fatty liver with cholestasis, and cirrhosis. Although variability in sampling and pathologist interpretation are of some concern, liver biopsy remains the gold standard for distinguishing between steatohepatitis and noninflammatory histologic patterns of injury that can also cause the clinical syndrome of alcohol-related hepatitis. Liver biopsy is not routinely recommended to ascertain a diagnosis of alcohol-related liver disease in patients with an uncertain alcohol history, because the histologic features of alcohol-related liver diseases can be found in other diseases, including nonalcoholic steatohepatitis and drug-induced liver injury.
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Affiliation(s)
- Nitzan C Roth
- Sandra Atlas Bass Center for Liver Diseases Department of Medicine Northwell Health, 400 Community Drive, Manhasset, NY 11030, USA.
| | - Jia Qin
- Department of Pathology, The Department of Veteran Affairs New York Harbor Healthcare System, 800 Poly Place, Brooklyn, NY 11209, USA
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21
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Wang M, Ma LJ, Yang Y, Xiao Z, Wan JB. n-3 Polyunsaturated fatty acids for the management of alcoholic liver disease: A critical review. Crit Rev Food Sci Nutr 2018; 59:S116-S129. [PMID: 30580553 DOI: 10.1080/10408398.2018.1544542] [Citation(s) in RCA: 91] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Excess alcohol exposure leads to alcoholic liver disease (ALD), a predominant cause of liver-related morbidity and mortality worldwide. In the past decade, increasing attention has been paid to understand the association between n-3 polyunsaturated fatty acids (n-3 PUFAs) and ALD. In this review, we summarize the metabolism of n-3 PUFAs, animal model of ALD, and the findings from recent studies determining the role of n-3 PUFAs in ALD as a possible treatment. The animal models of acute ethanol exposure, chronic ethanol exposure and chronic-plus-single binge ethanol feeding have been widely used to explore the impact of n-3 PUFAs. Although the results of studies regarding the role of n-3 PUFAs in ALD have been inconsistent or controversial, increasing evidence has demonstrated that n-3 PUFAs may be useful in alleviating alcoholic steatosis and alcohol-induced liver injury through multiple mechanisms, including decreased de novo lipogenesis and lipid mobilization from adipose tissue, enhanced mitochondrial fatty acid β-oxidation, reduced hepatic inflammation and oxidative stress, and promoted intestinal homeostasis, positively suggesting that n-3 PUFAs might be promising for the management of ALD. The oxidation of n-3 PUFAs ex vivo in an experimental diet was rarely considered in most n-3 PUFA-related studies, likely contributing to the inconsistent results. Thus, the role of n-3 PUFAs in ALD deserves greater research efforts and remains to be evaluated in randomized, placebo-controlled clinic trial. ABBREVIATION AA arachidonic acid ACC acetyl-CoA carboxylase ACLY ATP-citrate lyase ACO acyl-CoA oxidase ALA α-linolenic acid ALD alcoholic liver disease ALP alkaline phosphatase ALT alanine aminotransferase AMPK AMP-activated protein kinase AST aspartate aminotransferase ATGL adipose triglyceride lipase cAMP cyclic adenosine 3',5'-monophosphate COX cyclooxygenases CPT1 carnitine palmitoyltransferase 1 CYP2E1 cytochrome P450 2E1 DGAT2 diacylglycerol acyltransferase 2 DGLA dihomo-γ-linolenic acid DHA docosahexaenoic acid DPA docosapentaenoic acid DTA docosatetraenoic acid EPA eicosapentaenoic acid ER endoplasmic reticulum ETA eicosatetraenoic acid FAS fatty acid synthase FATPs fatty acid transporter proteins GLA,γ linolenic acid GPR120 G protein-coupled receptor 120 GSH glutathione; H&E haematoxylin-eosin; HO-1 heme oxygenase-1; HSL hormone-sensitive lipase; IL-6 interleukin-6 iNOS nitric oxide synthase LA linoleic acid LBP lipopolysaccharide binding protein LOX lipoxygenases LXR liver X receptor LXREs LXR response elements MCP-1 monocyte chemotactic protein-1 MTP microsomal triglyceride transfer protein MUFA monounsaturated fatty acids MyD88 myeloid differentiation factor 88 n-3 PUFAs omega-3 polyunsaturated fatty acid NAFLD nonalcoholic fatty liver disease NASH nonalcoholic steatohepatitis NF-κB transcription factor nuclear factor κB PDE3B phosphodiesterase 3B PPAR peroxisome proliferator-activated receptor ROS reactive oxygen species RXR retinoid X receptor SCD-1 stearyl CoA desaturase-1 SDA stearidonic acid SFA saturated fatty acids SIRT1 sirtuin 1 SOD superoxide dismutase SREBP sterol regulatory element-binding protein TB total bilirubin TC total cholesterol TG triacylglycerol TLR4 Toll-like receptor-4 TNF-α tumor necrosis factor-α VLDLR very low-density lipoprotein receptor WT wild type; ZO-1 zonula occludens-1.
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Affiliation(s)
- Meng Wang
- a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macao , China.,b Center for Drug Innovation and Discovery, College of Life Science, Hebei Normal University , Shijiazhuang , Hebei , China
| | - Li-Juan Ma
- a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macao , China
| | - Yan Yang
- c Department of Nutrition, School of Public Health , Sun Yat-Sen University , Guangzhou , China
| | - Zeyu Xiao
- d Collaborative Translational Medicine Collaborative Innovation Center, Department of Pharmacology and Chemical Biology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jian-Bo Wan
- a State Key Laboratory of Quality Research in Chinese Medicine , Institute of Chinese Medical Sciences, University of Macau , Macao , China
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Gao B, Zakhari S. Epidemiology and Pathogenesis of Alcoholic Liver Disease. ZAKIM AND BOYER'S HEPATOLOGY 2018:334-344.e3. [DOI: 10.1016/b978-0-323-37591-7.00022-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
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Schisandra sphenanthera extract (Wuzhi Tablet) protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice. Acta Pharm Sin B 2017; 7:583-592. [PMID: 28924552 PMCID: PMC5595297 DOI: 10.1016/j.apsb.2017.04.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2017] [Revised: 03/15/2017] [Accepted: 03/29/2017] [Indexed: 02/06/2023] Open
Abstract
Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available. Wuzhi Tablet (WZ), a preparation of extract from Schisandra sphenanthera that is a traditional hepato-protective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ and the target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.
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Key Words
- ALD, alcoholic liver disease
- ALT, alanine aminotransferase
- ARE, antioxidant response element
- AST, aspartate aminotransferase
- Alcoholic liver injury
- CYP2E1, cytochrome P450 2E1 enzyme
- EtOH, ethanol
- GCLC, glutamate–cysteine ligase catalytic subunit
- GCLM, glutamate–cysteine ligase modifier subunit
- GSH, glutathione
- H&E, hematoxylin and eosin
- HO-1, heme oxygenase-1
- NRF2, nuclear factor erythroid 2-related factor 2
- NRF2-ARE
- Oxidative stress
- SOD, superoxide dismutase
- Schisandra sphenanthera
- WZ, Wuzhi Tablet.
- Wuzhi Tablet
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Dunne PDJ, Forrest EH. Review article: recent insights into clinical decision-making in severe alcoholic hepatitis. Aliment Pharmacol Ther 2017; 46:274-281. [PMID: 28543549 DOI: 10.1111/apt.14144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Revised: 12/16/2016] [Accepted: 04/19/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND Alcoholic hepatitis is a severe acute manifestation of alcoholic liver disease with a high mortality. Management of patients with this condition has been a matter of controversy for many years; however, recent clinical studies have sought to improve the clinical approach to these patients. AIM To use these recent studies in order to guide clinical management. METHODS A MeSH search of Medline was performed to specifically identify recent studies which influenced clinical diagnosis, assessment and management of alcoholic hepatitis. RESULTS Fulfilment of clear clinical criteria including a minimum threshold of bilirubin, defined periods of jaundice and alcohol ingestion negates the need for liver biopsy in most patients. Corticosteroids improve short-term mortality only (28 day) with other factors such as abstinence likely to be significant in long-term outcome. Pentoxifylline is not an effective treatment. The Glasgow Alcoholic Hepatitis Score (GAHS) score can identify those patients likely to benefit from corticosteroids, but scores that include the evolution of bilirubin over 1 week of such treatment (such as the Lille Score) define "response". Underlying infection may contribute towards corticosteroid nonresponse and needs to be actively sought out and treated. Liver transplant remains controversial; however, it has been shown to be feasible in alcoholic hepatitis. CONCLUSIONS Recent studies have helped to define patients who may benefit from corticosteroid treatment. However, there remains a need for more accurate scores of prognosis and treatment response, and a clear need for alternative treatments for those patients not responding to corticosteroid therapy.
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Affiliation(s)
- P D J Dunne
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
| | - E H Forrest
- Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK
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25
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Li W, Amet T, Xing Y, Yang D, Liangpunsakul S, Puri P, Kamath P, Sanyal A, Shah V, Katz B, Radaeva S, Crabb D, Chalasani N, Yu Q. Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study. Hepatology 2017; 66:575-590. [PMID: 28466561 PMCID: PMC5548491 DOI: 10.1002/hep.29242] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Revised: 03/27/2017] [Accepted: 04/24/2017] [Indexed: 12/13/2022]
Abstract
Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma-induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. CONCLUSION AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).
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Affiliation(s)
- Wei Li
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Tohti Amet
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Yanyan Xing
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Dennis Yang
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Roudebush Veterans Administration Medical Center, Indianapolis, IN 46202
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202
| | - Puneet Puri
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Patrick Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, VA 23298
| | - Vijay Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905
| | - Barry Katz
- Department of Biostatistics, Indiana University School of Medicine and Richard M. Fairbanks School of Public Health, Indianapolis, IN 46202
| | - Svetlana Radaeva
- National Institute of Alcoholism and Alcohol Abuse, National Institutes of Health, Rockville, MD
| | - David Crabb
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
- Internal Medicine, Eskenazi Health, Indianapolis, IN 46202
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202-5175
| | - Qigui Yu
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202
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Teramura K, Kabuto M, Tanaka T, Fujimoto N. Adult-onset Still's disease-like condition due to alcoholic hepatitis and vitamin B deficiency. J Dermatol 2017; 44:e292-e293. [PMID: 28691376 DOI: 10.1111/1346-8138.13961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Kazuya Teramura
- Department of Dermatology, Shiga University of Medical Science, Otsu, Japan
| | - Miho Kabuto
- Department of Dermatology, Shiga University of Medical Science, Otsu, Japan
| | - Toshihiro Tanaka
- Department of Dermatology, Shiga University of Medical Science, Otsu, Japan
| | - Noriki Fujimoto
- Department of Dermatology, Shiga University of Medical Science, Otsu, Japan
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Fung P, Pyrsopoulos N. Emerging concepts in alcoholic hepatitis. World J Hepatol 2017; 9:567-585. [PMID: 28515843 PMCID: PMC5411952 DOI: 10.4254/wjh.v9.i12.567] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 02/21/2017] [Accepted: 03/12/2017] [Indexed: 02/06/2023] Open
Abstract
Severe alcoholic hepatitis is implicated as a costly, worldwide public health issue with high morbidity and mortality. The one-month survival for severe alcoholic hepatitis is low with mortality rates high as 30%-50%. Abstinence from alcohol is the recommended first-line treatment. Although corticosteroids remain as the current evidence based option for selected patients with discriminant function > 32, improvement of short-term survival rate may be the only benefit. Identification of individuals with risk factors for the development of severe alcoholic hepatitis may provide insight to the diverse clinical spectrum and prognosis of the disease. The understanding of the complex pathophysiologic processes of alcoholic hepatitis is the key to elucidating new therapeutic treatments. Newer research describes the use of gut microbiota modification, immune modulation, stimulation of liver regeneration, caspase inhibitors, farnesoid X receptors, and the extracorporeal liver assist device to aid in hepatocellular recovery. Liver transplantation can be considered as the last medical option for patients failing conventional medical interventions. Although the preliminary data is promising in patients with low risk of recividism, controversy remains due to organ scarcity. This review article comprehensively summarizes the epidemiology, pathophysiology, risk factors, and prognostic indicators of severe alcoholic hepatitis with a focus on the current and emerging therapeutics.
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Affiliation(s)
- Phoenix Fung
- Phoenix Fung, Nikolaos Pyrsopoulos, Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
| | - Nikolaos Pyrsopoulos
- Phoenix Fung, Nikolaos Pyrsopoulos, Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers New Jersey Medical School, Newark, NJ 07103, United States
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28
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Abstract
Malnutrition is associated with alcoholic liver disease (ALD) and related complications such as hepatic encephalopathy and increased rate of infections. Avoidance of prolonged fasting and overly restrictive diets is important to avoid poor nutrition. Adequate intake of calories, protein, and micronutrients via frequent small meals and evening supplements and/or enteral and parenteral nutrition when indicated has been associated with reduced mortality and morbidity in patients with ALD. Modification of protein/fat sources and composition in addition to probiotic supplementation are promising interventions for decreased progression of ALD and its complications.
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29
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Liangpunsakul S, Puri P, Shah VH, Kamath P, Sanyal A, Urban T, Ren X, Katz B, Radaeva S, Chalasani N, Crabb DW. Effects of Age, Sex, Body Weight, and Quantity of Alcohol Consumption on Occurrence and Severity of Alcoholic Hepatitis. Clin Gastroenterol Hepatol 2016; 14:1831-1838.e3. [PMID: 27320325 PMCID: PMC5108670 DOI: 10.1016/j.cgh.2016.05.041] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Revised: 05/24/2016] [Accepted: 05/31/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Only a minority of heavy drinking individuals develop alcoholic hepatitis (AH), for unclear reasons. We analyzed data from the Translational Research and Evolving Alcoholic Hepatitis Treatment cohort, consisting of subjects who drink heavily with normal results from liver tests (controls) and patients with AH. We examined risk factors for the development of AH including body mass index (BMI), drinking pattern and quantity, and sex. METHODS We compared data from 145 patients with AH and 124 controls based on BMI when they joined the cohort; groups were matched for sex and race. Drinking patterns were assessed using the timeline followback method, the Alcohol Use Disorders Identification Test, and the National Institute of Alcohol Abuse and Alcoholism 6-question survey. We performed univariable and multivariable analyses to assess the effects of these factors and their interaction in increasing the risk for AH. We also explored the association between PNPLA3 variants and AH. RESULTS Cases with AH were older (47 vs 44 y; P = .03). For nearly all measures of quantity of alcohol consumed or frequency of binge drinking, controls drank more heavily than cases with AH. We did not find an association between BMI, sex, drinking patterns, and the presence of AH. Age and BMI were independent predictors for the severity of AH. When we analyzed cases and controls of European ancestry, the PNPLA3 single-nucleotide polymorphism rs738409 was associated with risk for AH (odds ratio, 1.89; P = .007). CONCLUSIONS Compared with heavy drinkers without liver disease, subjects with AH consumed lower levels of alcohol and had less binge drinking, suggesting an increased sensitivity to the toxic effects of alcohol. The risk for AH may be associated with the PNPLA3 rs738409 polymorphism.
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Affiliation(s)
- Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Medicine, Roudebush Veterans Administration Medical Center, Indianapolis, Indiana.
| | - Puneet Puri
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Patrick Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Arun Sanyal
- Division of Gastroenterology and Hepatology, Department of Medicine, Virginia Commonwealth University, Richmond, Virginia
| | - Thomas Urban
- Division of Pharmacotherapy and Experimental Therapeutics, Center for Pharmacogenomics and Individualized Therapy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina
| | - Xiaowei Ren
- Department of Biostatistics, Richard M. Fairbanks School of Public Health, Indiana University School of Medicine, Indianapolis, Indiana
| | - Barry Katz
- Department of Biostatistics, Richard M. Fairbanks School of Public Health, Indiana University School of Medicine, Indianapolis, Indiana
| | - Svetlana Radaeva
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Rockville, Maryland
| | - Naga Chalasani
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - David W Crabb
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Eskenazi Health, Indianapolis, Indiana
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30
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Kim HY, Kim CW, Kim TY, Song DS, Sinn DH, Yoon EL, Jung YK, Suk KT, Lee SS, Lee CH, Kim TH, Kim JH, Yim HJ, Kim SE, Baik SK, Lee BS, Jang JY, Kim YS, Kim SG, Yang JM, Sohn JH, Lee HJ, Park SH, Choi EH, Kim DJ, Korean Acute-on-Chronic Liver Failure Study Group. Assessment of scoring systems for acute-on-chronic liver failure at predicting short-term mortality in patients with alcoholic hepatitis. World J Gastroenterol 2016; 22:9205-9213. [PMID: 27895407 PMCID: PMC5107601 DOI: 10.3748/wjg.v22.i41.9205] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/20/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To assess the performance of proposed scores specific for acute-on-chronic liver failure in predicting short-term mortality among patients with alcoholic hepatitis. METHODS We retrospectively collected data from 264 patients with clinically diagnosed alcoholic hepatitis from January to December 2013 at 21 academic hospitals in Korea. The performance for predicting short-term mortality was calculated for Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA), CLIF Consortium Organ Failure score (CLIF-C OFs), Maddrey's discriminant function (DF), age, bilirubin, international normalized ratio and creatinine score (ABIC), Glasgow Alcoholic Hepatitis Score (GAHS), model for end-stage liver disease (MELD), and MELD-Na. RESULTS Of 264 patients, 32 (12%) patients died within 28 d. The area under receiver operating characteristic curve of CLIF-SOFA, CLIF-C OFs, DF, ABIC, GAHS, MELD, and MELD-Na was 0.86 (0.81-0.90), 0.89 (0.84-0.92), 0.79 (0.74-0.84), 0.78 (0.72-0.83), 0.81 (0.76-0.86), 0.83 (0.78-0.88), and 0.83 (0.78-0.88), respectively, for 28-d mortality. The performance of CLIF-SOFA had no statistically significant differences for 28-d mortality. The performance of CLIF-C OFs was superior to that of DF, ABIC, and GAHS, while comparable to that of MELD and MELD-Na in predicting 28-d mortality. A CLIF-SOFA score of 8 had 78.1% sensitivity and 79.7% specificity, and CLIF-C OFs of 10 had 68.8% sensitivity and 91.4% specificity for predicting 28-d mortality. CONCLUSION CLIF-SOFA and CLIF-C OF scores performed well, with comparable predictive ability for short-term mortality compared to the commonly used scoring systems in patients with alcoholic hepatitis.
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31
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Im GY, Lucey MR. Practical Concerns and Controversies in the Management of Alcoholic Hepatitis. Gastroenterol Hepatol (N Y) 2016; 12:478-489. [PMID: 27917083 PMCID: PMC5114494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Recent advances in the treatment of alcoholic hepatitis (AH) have reinforced the utility of glucocorticoids, a treatment that has been in use for nearly 4 decades, to enhance short-term survival. As multi-institutional consortia research new therapeutic advances, this orphan disease, which afflicts younger patients and has poor outcomes, continues to be difficult to manage. AH has a protean clinical presentation and course, with various prediction models and treatment approaches that can challenge even experienced providers. This review addresses 4 key controversies and other practical issues associated with the diagnosis, prognosis, management, and treatment of patients with AH.
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Affiliation(s)
- Gene Y Im
- Dr Im is an assistant professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai and the Recanati/Miller Transplantation Institute in New York, New York. Dr Lucey is a professor of medicine and chief of the Division of Gastroenterology and Hepatology at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin
| | - Michael R Lucey
- Dr Im is an assistant professor of medicine in the Division of Liver Diseases at the Icahn School of Medicine at Mount Sinai and the Recanati/Miller Transplantation Institute in New York, New York. Dr Lucey is a professor of medicine and chief of the Division of Gastroenterology and Hepatology at the University of Wisconsin School of Medicine and Public Health in Madison, Wisconsin
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32
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Liangpunsakul S, Haber P, McCaughan G. Alcoholic Liver Disease in Asia, Europe, and North America. Gastroenterology 2016; 150:1786-97. [PMID: 26924091 PMCID: PMC4887319 DOI: 10.1053/j.gastro.2016.02.043] [Citation(s) in RCA: 123] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 02/05/2016] [Accepted: 02/09/2016] [Indexed: 12/16/2022]
Abstract
Alcoholic liver diseases comprise a spectrum of clinical disorders and changes in liver tissue that can be detected by pathology analysis. These range from steatosis to more severe signs and symptoms of liver disease associated with inflammation, such as those observed in patients with alcoholic hepatitis or cirrhosis. Although the relationship between alcohol consumption and liver disease is well established, severe alcohol-related morbidities develop in only a minority of people who consume alcohol in excess. Inter-individual differences in susceptibility to the toxic effects of alcohol have been studied extensively-they include pattern of alcohol consumption, sex, environmental factors (such as diet), and genetic factors, which vary widely among different parts of the world. Alcoholic liver disease is becoming more common in many parts of Asia, but is decreasing in Western Europe. Treatment approaches, including availability of medications, models of care, and approach to transplantation, differ among regions.
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Affiliation(s)
- Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Roudebush Veterans Administration Medical Center, Indianapolis, Indiana.
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Xu MJ, Cai Y, Wang H, Altamirano J, Chang B, Bertola A, Odena G, Lu J, Tanaka N, Matsusue K, Matsubara T, Mukhopadhyay P, Kimura S, Pacher P, Gonzalez FJ, Bataller R, Gao B. Fat-Specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans. Gastroenterology 2015; 149:1030-41.e6. [PMID: 26099526 PMCID: PMC4584194 DOI: 10.1053/j.gastro.2015.06.009] [Citation(s) in RCA: 119] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 05/29/2015] [Accepted: 06/09/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Alcoholic steatohepatitis (ASH) is the progressive form of alcoholic liver disease and may lead to cirrhosis and hepatocellular carcinoma. We studied mouse models and human tissues to identify molecules associated with ASH progression and focused on the mouse fat-specific protein 27 (FSP-27)/human cell death-inducing DFF45-like effector C (CIDEC) protein, which is expressed in white adipose tissues and promotes formation of fat droplets. METHODS C57BL/6N mice or mice with hepatocyte-specific disruption of Fsp27 (Fsp27(Hep-/-) mice) were fed the Lieber-Decarli ethanol liquid diet (5% ethanol) for 10 days to 12 weeks, followed by 1 or multiple binges of ethanol (5 or 6 g/kg) during the chronic feeding. Some mice were given an inhibitor (GW9662) of peroxisome proliferator-activated receptor γ (PPARG). Adenoviral vectors were used to express transgenes or small hairpin (sh) RNAs in cultured hepatocytes and in mice. Liver tissue samples were collected from ethanol-fed mice or from 31 patients with alcoholic hepatitis (AH) with biopsy-proved ASH and analyzed histologically and immunohistochemically and by transcriptome, immunoblotting, and real-time PCR analyses. RESULTS Chronic-plus-binge ethanol feeding of mice, which mimics the drinking pattern of patients with AH, produced severe ASH and mild fibrosis. Microarray analyses revealed similar alterations in expression of many hepatic genes in ethanol-fed mice and humans with ASH, including up-regulation of mouse Fsp27 (also called Cidec) and human CIDEC. Fsp27(Hep-/-) mice and mice given injections of adenovirus-Fsp27shRNA had markedly reduced ASH following chronic-plus-binge ethanol feeding. Inhibition of PPARG and cyclic AMP-responsive element binding protein H (CREBH) prevented the increases in Fsp27α and FSP27β mRNAs, respectively, and reduced liver injury in this chronic-plus-binge ethanol feeding model. Overexpression of FSP27 and ethanol exposure had synergistic effects in inducing production of mitochondrial reactive oxygen species and damage to hepatocytes in mice. Hepatic CIDEC mRNA expression was increased in patients with AH and correlated with the degree of hepatic steatosis and disease severity including mortality. CONCLUSIONS In mice, chronic-plus-binge ethanol feeding induces ASH that mimics some histological and molecular features observed in patients with AH. Hepatic expression of FSP27/CIDEC is highly up-regulated in mice following chronic-plus-binge ethanol feeding and in patients with AH; this up-regulation contributes to alcohol-induced liver damage.
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Affiliation(s)
- Ming-Jiang Xu
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Physiology and Pathophysiology, School of Basic Medical Science, Peking University, Beijing, China
| | - Yan Cai
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Hua Wang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland; Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - José Altamirano
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Liver Unit-Internal Medicine Department, Vall d'Hebron Hospital, Vall d'Hebron Institut de Recerca, Barcelona, Spain
| | - Binxia Chang
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Adeline Bertola
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Gemma Odena
- Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Jim Lu
- GoPath Diagnostics, LLC, Chicago, Illinois
| | - Naoki Tanaka
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Kimihiko Matsusue
- Faculty of Pharmaceutical Science, Fukuoka University, Fukuoka, Japan
| | - Tsutomu Matsubara
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Partha Mukhopadhyay
- Section of Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Pal Pacher
- Section of Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Ramon Bataller
- Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Liver Unit-Internal Medicine Department, Vall d'Hebron Hospital, Vall d'Hebron Institut de Recerca, Barcelona, Spain; Department of Nutrition, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina; Department of Medicine, Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
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Abstract
Alcoholic hepatitis (AH) is caused by acute inflammation of the liver in patients that consume excessive amounts of alcohol, usually in a background of cirrhosis. AH can range from mild to severe, life threatening disease with a high rate of short and long-term mortality. Prognostic models have been used to estimate mortality in order to identify those that may benefit from corticosteroids or pentoxifylline. This review focuses on the different prognostic models proposed. While limitations of the prognostic models exist, combining models may be beneficial in order to identify responders to therapy versus non-responders.
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Affiliation(s)
- Erik Rahimi
- Division of Gastroenterology, Hepatology and Nutrition, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 4.234, Houston, TX 77030 USA
| | - Jen-Jung Pan
- Division of Gastroenterology, Hepatology and Nutrition, University of Texas Medical School at Houston, 6431 Fannin Street, MSB 4.234, Houston, TX 77030 USA
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Gough G, Heathers L, Puckett D, Westerhold C, Ren X, Yu Z, Crabb DW, Liangpunsakul S. The Utility of Commonly Used Laboratory Tests to Screen for Excessive Alcohol Use in Clinical Practice. Alcohol Clin Exp Res 2015; 39:1493-500. [PMID: 26110815 DOI: 10.1111/acer.12780] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2014] [Accepted: 05/11/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND This current study was undertaken to carefully assess the accuracy of routinely used laboratory tests in detecting excessive/recent alcohol use. We also determined the kinetics of these markers in subjects who underwent an intensive alcohol rehabilitation program. METHODS The study cohort consisted of 210 nonexcessive drinkers, 272 excessive drinkers, and 76 with alcoholic cirrhosis. To determine the kinetics of these markers during alcohol abstinence, we followed 45 subjects with history of excessive alcohol use for 12 weeks during the intensive alcohol treatment program. RESULTS Percentage of carbohydrate deficient transferrin (%CDT) provided the highest diagnostic performance (area under the curve [AUC] 0.77) followed by gamma-glutamyl transferase (GGT) (AUC 0.68) to detect excessive drinkers. The percentage of excessive drinkers with aspartate aminotransferase:alanine aminotransferase (AST:ALT) > 2 was only 2%, whereas 51% of subjects with alcoholic cirrhosis had AST:ALT > 2. In the multivariate analysis, the levels of GGT and %CDT were associated with the level of alcohol consumed during the past 30 days. The levels of GGT, mean corpuscular volume (MCV), and %CDT were significantly lower compared to those at baseline before alcohol rehabilitation, whereas the AST, ALT, and AST:ALT ratio were unchanged. The percent reduction was ~2.7% (for MCV), 19% (for GGT), and 43% (for %CDT) at the end of the 12-week follow-up compared to the baseline. CONCLUSIONS %CDT are useful markers to screen for excessive alcohol use and for follow-up of abstinence. Most subjects with excessive alcohol use do not have a high AST:ALT ratio. Rather, the AST:ALT > 2 is suggestive of alcoholic cirrhosis. The performance of the %CDT to screen for heavy alcohol use is still not ideal. Further research to identify the noninvasive marker(s) (i.e., using proteomic or metabolomics approach) should be considered.
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Affiliation(s)
- Gina Gough
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Laura Heathers
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Deonna Puckett
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Chi Westerhold
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Xiaowei Ren
- Department of Biostatistics, Fairbanks School of Public Health, Indianapolis, Indiana
| | - Zhangsheng Yu
- Department of Biostatistics, Fairbanks School of Public Health, Indianapolis, Indiana
| | - David W Crabb
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.,Roudebush Veterans Administration Medical Center, Indianapolis, Indiana
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Liu M, Dou Y, Sun R, Zhang Y, Liu Y. Molecular mechanisms for alcoholic hepatitis based on analysis of gene expression profile. HEPATITIS MONTHLY 2015; 15:e27336. [PMID: 26045708 PMCID: PMC4451276 DOI: 10.5812/hepatmon.15(5)2015.27336] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/25/2015] [Revised: 03/04/2015] [Accepted: 03/29/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Alcoholic hepatitis (AH) is an acute manifestation of alcoholic liver disease with high mortality rates. OBJECTIVES Our aim was to study the molecular mechanisms of AH. MATERIALS AND METHODS The differentially expressed genes (DEGs) in liver between AH and control cases were identified by analyzing the GSE28619 microarray data using t-test. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and Gene Ontology (GO) enrichment analyses were performed using DAVID online tool. The protein-protein interaction (PPI) network was constructed using Search Tool for the Retrieval of Interacting Genes (STRING) and the subnetwork was identified by BioNet. Both PPI network and subnetwork were visualized using the Cytoscape software. RESULTS Total 908 DEGs (551 up- and 357 down-regulated DEGs) were obtained. The up-regulated DEGs were significantly enriched in 15 pathways and 112 GO biological processes. The down-regulated DEGs were significantly enriched in 22 pathways and 84 GO biological processes. The PPI network with 608 nodes and 2878 interactions was constructed and the subnetwork with 53 nodes and 131 interactions was also identified. The hub DEGs (TSPO, PPIB, NME1 and NME2) were extracted in this subnetwork. CONCLUSIONS TSPO might contribute to the liver damage and AH progression induced by mitochondrial dysfunction through oxidative stress of liver. TSPO interacted with PPIB might play important roles in liver damage in AH. The interaction between NME1 and NME2 might contribute to the transformation from AH to hepatocellular carcinoma.
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Affiliation(s)
- Minghui Liu
- Department of TCM, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yuchang Dou
- Department of TCM, China-Japan Union Hospital of Jilin University, Changchun, China
- Corresponding Author: Yuchang Dou, Department of TCM, China-Japan Union Hospital of Jilin University, Changchun, China. Tel: +86-43184995840, Fax: +86-43184995840, E-mail:
| | - Ran Sun
- Science Research Center, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yonggui Zhang
- Department of Gastroenterology, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Yansong Liu
- Department of TCM, China-Japan Union Hospital of Jilin University, Changchun, China
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Almeida JRDS, Araújo RC, Castilho GVD, Stahelin L, Pandolfi LDR, Silva CQ. Usefulness of a new prognostic index for alcoholic hepatitis. ARQUIVOS DE GASTROENTEROLOGIA 2015; 52:22-26. [PMID: 26017078 DOI: 10.1590/s0004-28032015000100006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 09/03/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND Alcoholic liver disease is a major cause of end-stage liver disease worldwide and severe forms of alcoholic hepatitis are associated with a high short-term mortality. Objectives To analyze the importance of age-bilirubin-INR-creatinine (ABIC) score as an index of mortality and predictor for complications in patients with alcoholic hepatitis. To evaluate its correlation with those complications, with risk of death, as well as the scores model for end stage liver disease (MELD) and Maddrey's discriminat function. METHODS A total of 46 medical records of patients who had been hospitalized with alcoholic hepatitis were assessed retrospectively with lab tests on admission and after seven days. Score calculations were carried out and analyzed as well. RESULTS The scores showed positive reciprocal correlation and were associated with both hepatic encephalopathy and ascites. ABIC index, which was classified as high risk, presented as a risk factor for these complications and for death. In univariate logistic regression analysis of mortality, the ABIC index at hospital admission odds ratio was 19.27, whereas after 7 days, it was 41.29. The average survival of patients with ABIC of low and intermediate risk was 61.1 days, and for those with high risk, 26.2 days. CONCLUSIONS ABIC index is a predictor factor for complications such as ascites and hepatic encephalopathy, as well as for risk of death. Thus, it is a useful tool for clinical practice.
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Affiliation(s)
| | - Roberta Chaves Araújo
- Departamento de Clínica - Gastroenterologia, Faculdade de Ciências Médicas, Universidade de Campinas, Campinas, SP, Brasil
| | - Giane Vieira de Castilho
- Departamento de Clínica - Gastroenterologia, Faculdade de Ciências Médicas, Universidade de Campinas, Campinas, SP, Brasil
| | - Letícia Stahelin
- Departamento de Clínica - Gastroenterologia, Faculdade de Ciências Médicas, Universidade de Campinas, Campinas, SP, Brasil
| | - Lívia Dos Reis Pandolfi
- Departamento de Clínica - Gastroenterologia, Faculdade de Ciências Médicas, Universidade de Campinas, Campinas, SP, Brasil
| | - Cecília Queiroz Silva
- Departamento de Clínica - Gastroenterologia, Faculdade de Ciências Médicas, Universidade de Campinas, Campinas, SP, Brasil
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