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Amiri S, Yaghoobi A, Khan MAB. Prevalence of alcohol use and smoking in eating disorders: a systematic review and meta-analysis. JOURNAL OF SUBSTANCE USE 2025:1-20. [DOI: 10.1080/14659891.2024.2446933] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Accepted: 11/28/2024] [Indexed: 02/13/2025]
Affiliation(s)
- Sohrab Amiri
- Spiritual Health Research Center, Life Style Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abolghasem Yaghoobi
- Department of Psychology, Faculty of Economics and Social Sciences, Bu-Ali Sina University, Hamedan, Iran
| | - Moien AB Khan
- Health and Wellness Research Group, Department of Family Medicine, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, UAE
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Åberg F, Jiang ZG, Cortez-Pinto H, Männistö V. Alcohol-associated liver disease-Global epidemiology. Hepatology 2024; 80:1307-1322. [PMID: 38640041 DOI: 10.1097/hep.0000000000000899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 03/23/2024] [Indexed: 04/21/2024]
Abstract
Alcohol-associated liver disease (ALD), as highlighted in this narrative review, is a major public health concern, increasingly impacting global disease burden and premature mortality. In 2019, ALD accounted for the loss of 11 million life-years worldwide. The rising number of deaths and disability-adjusted life-years attributed to ALD, particularly pronounced in the United States, are alarming. Projections suggest that the economic impact of ALD, as seen in the United States, could potentially double by 2040. ALD is increasingly prevalent among younger adults (20-45 y) and has become the leading cause of liver transplantation in both United States and Europe. During the COVID-19 pandemic, the existing trend was further amplified as high-risk drinking patterns coincided with a rise in hospital admissions for alcohol-associated hepatitis and increased ALD-related mortality. The prevalence of ALD is estimated at 3.5% in the general population, 26.0% among hazardous drinkers, and 55.1% among those with alcohol use disorders. Alarmingly, 5-year mortality rates for patients with ALD exceed 50%, with even higher rates in more advanced disease stages. Methodological challenges, such as underreporting, diagnostic difficulties, and variability in registry data quality, complicate the accurate assessment of the impact of ALD. Additionally, the contribution of alcohol to the progression of other liver diseases is often under acknowledged in health care registries, leading to a significant underestimation of its broader implications for liver health. Addressing the growing ALD concern requires robust public health initiatives, heightened awareness, refined diagnostic techniques, and comprehensive epidemiological studies. These measures are vital to tackle the increasing prevalence of ALD and mitigate its extensive impact on individuals and health care systems.
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Affiliation(s)
- Fredrik Åberg
- Transplantation and Liver Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Z Gordon Jiang
- Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Helena Cortez-Pinto
- Clínica Universitária de Gastrenterologia, Faculdade de Medicina, Universidade de Lisboa, Portugal
| | - Ville Männistö
- Department of Medicine, University of Eastern Finland, Kuopio, Finland
- Department of Medicine, Kuopio University Hospital, Kuopio, Finland
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Mullish BH, Thursz MR. Alcohol-associated liver disease: Emerging therapeutic strategies. Hepatology 2024; 80:1372-1389. [PMID: 38922808 DOI: 10.1097/hep.0000000000000986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 06/08/2024] [Indexed: 06/28/2024]
Abstract
The large and growing burden of alcohol-associated liver disease-and the considerable burden of morbidity and mortality associated with it-has been a drive toward ongoing research into novel strategies for its treatment, with a particular focus upon alcohol-associated hepatitis (AH). Management of alcohol-use disorder forms the central pillar of alcohol-associated liver disease care, with evidence-based psychological and pharmacological approaches being well established, and certain models demonstrating improved clinical outcomes when hepatology and addiction services are co-located. Corticosteroids have previously been used somewhat indiscriminately in patients with severe AH, but effective tools now exist to assess early response (and limit futile ongoing exposure). Techniques to predict risk of corticosteroid-related infection are also available, although current clinical strategies to mitigate this risk are limited. A variety of novel therapeutic approaches to AH are at different phases of trials and evidence gathering, with some of the most promising signals related to cytokine manipulation, epigenetic modulation, and targeting of the gut microbiota (ie, by means of fecal microbiota transplant). While remaining an ongoing source of debate, early liver transplant in severe AH has grown in interest and acceptability over the past decade as evidence supporting its efficacy builds, in the process challenging paradigms about mandatory pretransplant sobriety periods. However, uncertainty remains regarding the optimal selection criteria, and whether liver transplant has a role for only a highly limited proportion of patients with AH or more widespread application. This review aims to provide an overview of this fast-moving field.
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Affiliation(s)
- Benjamin H Mullish
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
- Department of Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
| | - Mark R Thursz
- Section of Hepatology and Gastroenterology, Department of Metabolism, Digestion and Reproduction, Division of Digestive Diseases, Faculty of Medicine, Imperial College London, London, United Kingdom
- Department of Hepatology, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, United Kingdom
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Sun YQ, Wu Y, Li MR, Wei YY, Guo M, Zhang ZL. Elafibranor alleviates alcohol-related liver fibrosis by restoring intestinal barrier function. World J Gastroenterol 2024; 30:4660-4668. [PMID: 39575408 PMCID: PMC11572637 DOI: 10.3748/wjg.v30.i43.4660] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/29/2024] [Accepted: 10/18/2024] [Indexed: 10/31/2024] Open
Abstract
We discuss the article by Koizumi et al published in the World Journal of Gastroenterology. Our focus is on the therapeutic targets for fibrosis associated with alcohol-related liver disease (ALD) and the mechanism of action of elafibranor (EFN), a dual agonist of peroxisome proliferator-activated receptor α (PPARα) and peroxisome PPAR δ (PPARδ). EFN is currently in phase III clinical trials for the treatment of metabolic dysfunction-associated fatty liver disease and primary biliary cholangitis. ALD progresses from alcoholic fatty liver to alcoholic steatohepatitis (ASH), with chronic ASH eventually leading to fibrosis, cirrhosis, and, in some cases, hepatocellular carcinoma. The pathogenesis of ALD is driven by hepatic steatosis, oxidative stress, and acetaldehyde toxicity. Alcohol consumption disrupts lipid metabolism by inactivating PPARα, exacerbating the progression of ALD. EFN primarily activates PPARα, promoting lipolysis and β-oxidation in ethanol-stimulated HepG2 cells, which significantly reduces hepatic steatosis, apoptosis, and fibrosis in an ALD mouse model. Additionally, alcohol disrupts the gut-liver axis at several interconnected levels, contributing to a proinflammatory environment in the liver. EFN helps alleviate intestinal hyperpermeability by restoring tight junction protein expression and autophagy, inhibiting apoptosis and inflammatory responses, and enhancing intestinal barrier function through PPARδ activation.
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Affiliation(s)
- Yu-Qi Sun
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Yang Wu
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Meng-Ran Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Yu-Yao Wei
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Mei Guo
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
| | - Zi-Li Zhang
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu Province, China
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Verma N, Vinod AP, Singal AK. The pharmacological management of alcohol-related cirrhosis: what's new? Expert Opin Pharmacother 2024; 25:1923-1941. [PMID: 39360770 DOI: 10.1080/14656566.2024.2409941] [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: 06/28/2024] [Accepted: 09/24/2024] [Indexed: 10/05/2024]
Abstract
INTRODUCTION Alcohol use disorder (AUD) is present in the majority of patients with alcohol-associated liver disease (ALD), which leads to about 50% of cirrhosis-related hospitalizations and over 25% of deaths worldwide. Patients with ALD often present at an advanced stage, like cirrhosis with its complications and alcohol-associated hepatitis (AH), which has high short-term mortality. Current treatments are limited, with the limited benefit of glucocorticoids only in the short-term among patients with AH, highlighting an urgent need for novel therapies. AREAS COVERED This review applies the PIRO (Predisposition, Injury, Response, Organ dysfunction) concept to ALD, understanding an ongoing process of liver damage, and opportunities to address and halt the progression. We also highlight the significance of treating AUD to improve long-term outcomes in ALD. EXPERT OPINION Personalized therapies targeting specific genetic profiles and multiple pathogenic pathways are crucial in managing ALD. Emerging therapies like gut-liver-brain axis modulators like fecal microbiota transplant and probiotics, interleukin-22, granulocyte-colony stimulating factor (G-CSF) and stem cells, epigenetic regulators of inflammation and regeneration are encouraging with the potential of efficacy in patients with ALD. Liver transplantation (LT) is a definitive therapy for advanced cirrhosis with increasing impetus on early LT select patients with active alcohol use.
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Affiliation(s)
- Nipun Verma
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwin P Vinod
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Ashwani K Singal
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Louisville School of Medicine, Louisville, KY, USA
- Department of Transplant Hepatology, Jewish Hospital and Trager Transplant Center, Louisville, Kentucky, USA
- Department of Research, Veteran Affairs Medical Center, Sioux Falls, SD, USA
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Jophlin LL, Singal AK, Bataller R, Wong RJ, Sauer BG, Terrault NA, Shah VH. ACG Clinical Guideline: Alcohol-Associated Liver Disease. Am J Gastroenterol 2024; 119:30-54. [PMID: 38174913 PMCID: PMC11040545 DOI: 10.14309/ajg.0000000000002572] [Citation(s) in RCA: 54] [Impact Index Per Article: 54.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Accepted: 10/04/2023] [Indexed: 01/05/2024]
Abstract
ABSTRACT Alcohol-associated liver disease (ALD) is the most common cause of advanced hepatic disease and frequent indication for liver transplantation worldwide. With harmful alcohol use as the primary risk factor, increasing alcohol use over the past decade has resulted in rapid growth of the ALD-related healthcare burden. The spectrum of ALD ranges from early asymptomatic liver injury to advanced disease with decompensation and portal hypertension. Compared with those with other etiologies of liver disease, patients with ALD progress faster and more often present at an advanced stage. A unique phenotype of advanced disease is alcohol-associated hepatitis (AH) presenting with rapid onset or worsening of jaundice, and acute on chronic liver failure in severe forms conveying a 1-month mortality risk of 20%-50%. The model for end stage disease score is the most accurate score to stratify AH severity (>20 defined as severe disease). Corticosteroids are currently the only available therapeutic with proven efficacy for patients with severe AH, providing survival benefit at 1 month in 50%-60% of patients. Abstinence of alcohol use, a crucial determinant of long-term outcomes, is challenging to achieve in ALD patients with concurrent alcohol use disorder (AUD). As patients with ALD are rarely treated for AUD, strategies are needed to overcome barriers to AUD treatment in patients with ALD and to promote a multidisciplinary integrated care model with hepatology, addiction medicine providers, and social workers to comprehensively manage the dual pathologies of liver disease and of AUD. Liver transplantation, a definitive treatment option in patients with advanced cirrhosis, should be considered in selected patients with AH, who are unresponsive to medical therapy and have a low risk of relapse to posttransplant alcohol use. Level of evidence and strength of recommendations were evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations system. This guideline was developed under the American College of Gastroenterology Practice Parameters Committee.
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Affiliation(s)
- Loretta L. Jophlin
- Division of Gastroenterology, Hepatology and Nutrition, University of Louisville Health, Louisville, Kentucky, USA
| | - Ashwani K. Singal
- Division of Gastroenterology and Hepatology, University of South Dakota, Sioux Falls, South Dakota, USA
| | - Ramon Bataller
- Liver Unit, Department of Digestive and Metabolic Diseases, Hospital Clinic, Barcelona, Spain
| | - Robert J. Wong
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA
| | - Bryan G. Sauer
- Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA
| | - Norah A. Terrault
- Division of Gastrointestinal and Liver Diseases, University of Southern California, Los Angeles, California, USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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Baweja S, Mittal A, Thangariyal S, Subudhi PD, Gautam S, Kaul R. Unveiling the effect of estrogen receptors in alcoholic liver disease: A novel outlook. LIVER RESEARCH 2023; 7:333-341. [PMID: 39958778 PMCID: PMC11791908 DOI: 10.1016/j.livres.2023.10.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Revised: 08/19/2023] [Accepted: 10/23/2023] [Indexed: 01/11/2025]
Abstract
Alcoholic liver disease (ALD) has a multifaceted development, progressing from alcoholic steatosis to alcoholic hepatitis and ultimately to alcoholic cirrhosis, irreversible liver damage that can even result in hepatocellular carcinoma. The prevalence of ALD is increasing globally, particularly among middle-aged adults. Gender-based studies have revealed that ALD affects more men; however, disease progression differs between men and women. Despite this, the molecular understanding of alcohol-induced liver injury among genders and its association with changes in sex hormone metabolism, particularly with estrogen and estrogen receptors (ERs) in ALD, remains poor. This review focuses on experimental and human studies describing alcohol and its association with estrogen metabolism and signaling via ERs. Chronic alcohol consumption affects the immune response, and whether estrogen has any contributory effect remains inadequately studied. This review also discusses various therapeutic approaches currently in use and future approaches that can affect the response or progression via estrogen signaling. The role of gender on alcohol consumption and its association with steroid hormones must be elucidated for a better understanding of the pathogenesis of ALD, the development of effective therapeutic approaches, and better disease management in both men and women, as ALD remains a major public health concern.
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Affiliation(s)
- Sukriti Baweja
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Ashmit Mittal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Swati Thangariyal
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - P. Debishree Subudhi
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Shivani Gautam
- Department of Molecular and Cellular Medicine, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Rashmi Kaul
- Department of Biochemistry and Microbiology, Oklahoma State University Center for Health Sciences, Tulsa, OK, USA
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Norden-Krichmar TM, Rotroff D, Schwantes-An TH, Bataller R, Goldman D, Nagy LE, Liangpunsakul S. Genomic approaches to explore susceptibility and pathogenesis of alcohol use disorder and alcohol-associated liver disease. Hepatology 2023:01515467-990000000-00586. [PMID: 37796138 PMCID: PMC10985049 DOI: 10.1097/hep.0000000000000617] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 08/13/2023] [Indexed: 10/06/2023]
Abstract
Excessive alcohol use is a major risk factor for the development of an alcohol use disorder (AUD) and contributes to a wide variety of other medical illnesses, including alcohol-associated liver disease (ALD). Both AUD and ALD are complex and causally interrelated diseases, and multiple factors other than alcohol consumption are implicated in the disease pathogenesis. While the underlying pathophysiology of AUD and ALD is complex, there is substantial evidence for a genetic susceptibility of both diseases. Current genome-wide association studies indicate that the genes associated with clinical AUD only poorly overlap with the genes identified for heavy drinking and, in turn, neither overlap with the genes identified for ALD. Uncovering the main genetic factors will enable us to identify molecular drivers underlying the pathogenesis, discover potential targets for therapy, and implement patient care early in disease progression. In this review, we described multiple genomic approaches and their implications to investigate the susceptibility and pathogenesis of both AUD and ALD. We concluded our review with a discussion of the knowledge gaps and future research on genomic studies in these 2 diseases.
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Affiliation(s)
| | - Daniel Rotroff
- Department of Quantitative Health Sciences, Cleveland Clinic, Cleveland, OH
| | - Tae-Hwi Schwantes-An
- Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN
| | - Ramon Bataller
- Liver Unit, Institut of Digestive and Metabolic Diseases, Hospital Clinic, Barcelona, Spain
- Institut d’Investigacions Biomediques August Pi i Sunyer (IDIBAPS)
| | - David Goldman
- Laboratory of Neurogenetics and Office of the Clinical Director, National Institute on Alcohol Abuse and Alcoholism, Rockville, MD
| | - Laura E. Nagy
- Center for Liver Disease Research, Department of Inflammation and Immunity, Cleveland Clinic, Cleveland, OH
- Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH
- Department of Molecular Medicine, Case Western Reserve University, Cleveland, OH
| | - Suthat Liangpunsakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Indianapolis, IN
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN
- Roudebush Veterans Administration Medical Center, Indianapolis, IN
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Staufer K, Stauber RE. Steatotic Liver Disease: Metabolic Dysfunction, Alcohol, or Both? Biomedicines 2023; 11:2108. [PMID: 37626604 PMCID: PMC10452742 DOI: 10.3390/biomedicines11082108] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 08/27/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD), both of them accounting for fatty liver disease (FLD), are among the most common chronic liver diseases globally, contributing to substantial public health burden. Both NAFLD and ALD share a similar picture of clinical presentation yet may have differences in prognosis and treatment, which renders early and accurate diagnosis difficult but necessary. While NAFLD is the fastest increasing chronic liver disease, the prevalence of ALD has seemingly remained stable in recent years. Lately, the term steatotic liver disease (SLD) has been introduced, replacing FLD to reduce stigma. SLD represents an overarching term to primarily comprise metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), as well as alcohol-related liver disease (ALD), and MetALD, defined as a continuum across which the contribution of MASLD and ALD varies. The present review discusses current knowledge on common denominators of NAFLD/MASLD and ALD in order to highlight clinical and research needs to improve our understanding of SLD.
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Affiliation(s)
- Katharina Staufer
- Division of Transplantation, Department of General Surgery, Medical University of Vienna, 1090 Vienna, Austria
| | - Rudolf E Stauber
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, 8010 Graz, Austria
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Gentry AE, Alexander JC, Ahangari M, Peterson RE, Miles MF, Bettinger JC, Davies AG, Groteweil M, Bacanu SA, Kendler KS, Riley BP, Webb BT. Case-only exome variation analysis of severe alcohol dependence using a multivariate hierarchical gene clustering approach. PLoS One 2023; 18:e0283985. [PMID: 37098020 PMCID: PMC10128939 DOI: 10.1371/journal.pone.0283985] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/21/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Variation in genes involved in ethanol metabolism has been shown to influence risk for alcohol dependence (AD) including protective loss of function alleles in ethanol metabolizing genes. We therefore hypothesized that people with severe AD would exhibit different patterns of rare functional variation in genes with strong prior evidence for influencing ethanol metabolism and response when compared to genes not meeting these criteria. OBJECTIVE Leverage a novel case only design and Whole Exome Sequencing (WES) of severe AD cases from the island of Ireland to quantify differences in functional variation between genes associated with ethanol metabolism and/or response and their matched control genes. METHODS First, three sets of ethanol related genes were identified including those a) involved in alcohol metabolism in humans b) showing altered expression in mouse brain after alcohol exposure, and altering ethanol behavioral responses in invertebrate models. These genes of interest (GOI) sets were matched to control gene sets using multivariate hierarchical clustering of gene-level summary features from gnomAD. Using WES data from 190 individuals with severe AD, GOI were compared to matched control genes using logistic regression to detect aggregate differences in abundance of loss of function, missense, and synonymous variants, respectively. RESULTS Three non-independent sets of 10, 117, and 359 genes were queried against control gene sets of 139, 1522, and 3360 matched genes, respectively. Significant differences were not detected in the number of functional variants in the primary set of ethanol-metabolizing genes. In both the mouse expression and invertebrate sets, we observed an increased number of synonymous variants in GOI over matched control genes. Post-hoc simulations showed the estimated effects sizes observed are unlikely to be under-estimated. CONCLUSION The proposed method demonstrates a computationally viable and statistically appropriate approach for genetic analysis of case-only data for hypothesized gene sets supported by empirical evidence.
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Affiliation(s)
- Amanda Elswick Gentry
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Jeffry C. Alexander
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Mohammad Ahangari
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Integrative Life Sciences Ph.D. Program, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Roseann E. Peterson
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Psychiatry and Behavioral Sciences, Institute for Genomics in Health, SUNY Downstate Health Sciences University, Brooklyn, New York, United States of America
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Michael F. Miles
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Jill C. Bettinger
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Andrew G. Davies
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Mike Groteweil
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Silviu A. Bacanu
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Kenneth S. Kendler
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Brien P. Riley
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Psychiatry, Virginia Commonwealth University, Richmond, Virginia, United States of America
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia, United States of America
| | - Bradley T. Webb
- VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, Virginia, United States of America
- GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, North Caroline, United States of America
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Kendler KS, Ohlsson H, Sundquist J, Sundquist K. The impact of sex, age at onset, recurrence, mode of ascertainment and medical complications on the family genetic risk score profiles for alcohol use disorder. Psychol Med 2023; 53:1732-1740. [PMID: 34620257 DOI: 10.1017/s0033291721003317] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Alcohol use disorder (AUD) is clinically heterogeneous. We examine its potential genetic heterogeneity as a function of sex, age, clinical features and mode of ascertainment. METHODS In the Swedish population born 1932-1995 (n = 5 829 952), we examined the genetic risk profiles for AUD, major depression (MD), anxiety disorders, bipolar disorder, drug use disorder (DUD), attention deficit-hyperactivity disorder (ADHD) and criminal behavior (CB) in 361 124 cases of AUD subdivided by sex, age at onset (AAO), recurrence, mode of ascertainment and medical complications. Family genetic risk scores (FGRS), calculated from 1st to 5th-degree relatives controlling of cohabitation, assesses genetic risk from phenotypes in the family, not from DNA variants. RESULTS FGRS profiles differed modestly across sex with all scores higher in females. Differences were more pronounced for AAO and recurrence with the FGRS for AUD, DUD, ADHD and CB substantially higher in cases with early AAO or high recurrence rates. Genetic profiles differed considerably by mode of ascertainment, with higher FGRS for AUD and most other disorders in patients seen in hospital v. primary care settings. Cases of AUD with medical complications had higher FGRS for AUD. AUD cases comorbid with MD and DUD had higher FGRS risk for AUD, but this genetic may be less specific given increases in FGRS for multiple other disorders. CONCLUSIONS From a genetic perspective, AUD differs substantially as a function of AAO, recurrence, mode of ascertainment and patterns of comorbidity, suggesting caution in cross-sample comparisons of AUD cohorts that differ in these features.
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Affiliation(s)
- Kenneth S Kendler
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA
- Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA
| | - Henrik Ohlsson
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
- Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Functional Pathology, Center for Community-based Healthcare Research and Education (CoHRE), School of Medicine, Shimane University, Matsue, Japan
| | - Kristina Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
- Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, USA
- Department of Functional Pathology, Center for Community-based Healthcare Research and Education (CoHRE), School of Medicine, Shimane University, Matsue, Japan
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Gómez-Medina C, Melo L, Martí-Aguado D, Bataller R. Subclinical versus advanced forms of alcohol-related liver disease: Need for early detection. Clin Mol Hepatol 2023; 29:1-15. [PMID: 35430784 PMCID: PMC9845676 DOI: 10.3350/cmh.2022.0017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 04/11/2022] [Indexed: 02/02/2023] Open
Abstract
Alcohol-related liver disease (ALD) consists of a wide spectrum of clinical manifestations and pathological features, ranging from asymptomatic patients to decompensated cirrhosis and hepatocellular carcinoma. Patients with heavy alcohol intake and advanced fibrosis often develop a subacute form of liver failure called alcohol-induced hepatitis (AH). Globally, most patients with ALD are identified at late stages of the disease, limiting therapeutic interventions. Thus, there is a need for early detection of ALD patients, which is lacking in most countries. The identification of alcohol misuse is hampered by the existence of alcohol underreporting by many patients. There are useful biomarkers that can detect recent alcohol use. Moreover, there are several non-invasive techniques to assess the presence of advanced fibrosis among patients with alcohol misuse, which could identify patients at high risk of liver related events or early death. In this review, we discuss differences between early stages of ALD and AH as the cornerstone of advanced forms. A global overview of epidemiological, anthropometric, clinical, analytical, histological, and molecular differences is summarized in this article. We propose that campaigns aimed at identifying patients with subclinical forms can prevent the development of life-threatening forms.
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Affiliation(s)
- Concepción Gómez-Medina
- Division of Gastroenterology and Hepatology, Medical Department, Clinic University Hospital of Valencia, Valencia, Spain
| | - Luma Melo
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - David Martí-Aguado
- Division of Gastroenterology and Hepatology, Medical Department, Clinic University Hospital of Valencia, Valencia, Spain
| | - Ramón Bataller
- Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA,Corresponding author : Ramón Bataller Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, 200 Lothrop Street, BSTW Suite 1116, Pittsburgh, PA 15213, USA Tel: +1-412-383-4241, Fax: +1-412-648-4055, E-mail:
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13
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Hayat U, Siddiqui AA, Farhan ML, Haris A, Hameed N. Genome Editing and Fatty Liver. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1396:191-206. [DOI: 10.1007/978-981-19-5642-3_13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/03/2022]
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14
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NAFLD: genetics and its clinical implications. Clin Res Hepatol Gastroenterol 2022; 46:102003. [PMID: 35963605 DOI: 10.1016/j.clinre.2022.102003] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 07/28/2022] [Accepted: 08/09/2022] [Indexed: 02/04/2023]
Abstract
Worldwide non-alcoholic fatty liver disease (NAFLD) is recognized as the most common type of liver disease and its burden increasing at an alarming rate. NAFLD entails steatosis, fibrosis, cirrhosis, and, finally, hepatocellular carcinoma (HCC). The substantial inter-patient variation during disease progression is the hallmark of individuals with NAFLD. The variability of NAFLD development and related complications among individuals is determined by genetic and environmental factors. Genome-wide association studies (GWAS) have discovered reproducible and robust associations between gene variants such as PNPLA3, TM6SF2, HSD17B13, MBOAT7, GCKR and NAFLD. Evidences have provided the new insights into the NAFLD biology and underlined potential pharmaceutical targets. Ideally, the candidate genes associated with the hereditability of NAFLD are mainly involved in assembly of lipid droplets, lipid remodeling, lipoprotein packing and secretion, redox status mitochondria, and de novo lipogenesis. In recent years, the ability to translate genetics into a clinical context has emerged substantially by combining genetic variants primarily associated with NAFLD into polygenic risk scores (PRS). These score in combination with metabolic factors could be utilized to identify the severe liver diseases in patients with the gene regulatory networks (GRNs). Hereby, we even have highlighted the current understanding related to the schedule therapeutic approach of an individual based on microbial colonization and dysbiosis reversal as a therapy for NAFLD. The premise of this review is to concentrate on the potential of genetic factors and their translation into the design of novel therapeutics, as well as their implications for future research into personalized medications using microbiota.
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Balakrishnan R, Mohammed V, Veerabathiran R. The role of genetic mutation in alcoholic liver disease. EGYPTIAN LIVER JOURNAL 2022. [DOI: 10.1186/s43066-022-00175-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
Alcoholic liver disease (ALD) is the world’s most common type of liver disease caused due to overconsumption of alcohol. The liver supports the best level of tissue damage by hefty drinking since it is the binding site of ethanol digestion. This disease can progress to alcoholic steatohepatitis from alcoholic fatty liver, which implies steatosis has become the most punctual reaction to hefty drinking and is portrayed by the deposition of fat hepatocytes. In addition, steatosis can advance to steatohepatitis, a more extreme, provocative sort of liver damage described by hepatic inflammation. Constant and unnecessary liquor utilization delivers a wide range of hepatic sores, fibrosis and cirrhosis, and sometimes hepatocellular carcinoma. Most people consuming > 40 g of liquor each day create alcoholic fatty liver (AFL); notwithstanding, just a subset of people will grow further developed infection. Hereditary, epigenetic, and non-hereditary components may clarify the impressive interindividual variety in the ALD phenotype.
Main body
This systematic review is to classify new candidate genes associated with alcoholic liver disorders, such as RASGRF2, ALDH2, NFE2L2, ADH1B, PNPLA3, DRD2, MTHFR, TM6SF2, IL1B, and CYP2E1, MBOAT7 as well as to revise the functions of each gene in its polymorphic sequence. The information obtained from the previously published articles revealed the crucial relationship between the genes and ALD and discussed each selected gene’s mechanism.
Conclusion
The aim of this review is to highlight the candidate genes associated with the ALD, and the evidence of this study is to deliberate the part of genetic alterations and modifications that can serve as an excellent biological maker, risk predictors, and therapeutic targets for this disease.
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Schnabl B, Arteel GE, Stickel F, Hengstler J, Vartak N, Ghallab A, Dooley S, Li Y, Schwabe RF. Liver specific, systemic and genetic contributors to alcohol-related liver disease progression. ZEITSCHRIFT FUR GASTROENTEROLOGIE 2022; 60:36-44. [PMID: 35042252 PMCID: PMC8941985 DOI: 10.1055/a-1714-9330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Alcohol-related liver disease (ALD) impacts millions of patients worldwide each year and the numbers are increasing. Disease stages range from steatosis via steatohepatitis and fibrosis to cirrhosis, severe alcohol-associated hepatitis and liver cancer. ALD is usually diagnosed at an advanced stage of progression with no effective therapies. A major research goal is to improve diagnosis, prognosis and also treatments for early ALD. This however needs prioritization of this disease for financial investment in basic and clinical research to more deeply investigate mechanisms and identify biomarkers and therapeutic targets for early detection and intervention. Topics of interest are communication of the liver with other organs of the body, especially the gut microbiome, the individual genetic constitution, systemic and liver innate inflammation, including bacterial infections, as well as fate and number of hepatic stellate cells and the composition of the extracellular matrix in the liver. Additionally, mechanical forces and damaging stresses towards the sophisticated vessel system of the liver, including the especially equipped sinusoidal endothelium and the biliary tract, work together to mediate hepatocytic import and export of nutritional and toxic substances, adapting to chronic liver disease by morphological and functional changes. All the aforementioned parameters contribute to the outcome of alcohol use disorder and the risk to develop advanced disease stages including cirrhosis, severe alcoholic hepatitis and liver cancer. In the present collection, we summarize current knowledge on these alcohol-related liver disease parameters, excluding the aspect of inflammation, which is presented in the accompanying review article by Lotersztajn and colleagues.
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Affiliation(s)
- Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, United States
- Department of Medicine, VA San Diego Healthcare System, San Diego, United States
| | - Gavin E Arteel
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, United States
- Pittsburgh Liver Research Center, Pittsburgh, United States
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland
| | - Jan Hengstler
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund University, Dortmund, Germany
| | - Nachiket Vartak
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund University, Dortmund, Germany
| | - Ahmed Ghallab
- Systems Toxicology, Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund University, Dortmund, Germany
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Steven Dooley
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Yujia Li
- Department of Medicine II, Section Molecular Hepatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, United States
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17
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Khan S, Cain O, Rajoriya N. Alcohol Related Liver Disease. MEN’S HEALTH AND WELLBEING 2022:163-191. [DOI: 10.1007/978-3-030-84752-4_11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Edwards AC, Sundquist K, Sundquist J, Kendler KS, Lönn SL. Genetic and environmental influences on the progression from alcohol use disorder to alcohol-related medical conditions. Alcohol Clin Exp Res 2021; 45:2528-2535. [PMID: 34923650 PMCID: PMC8712390 DOI: 10.1111/acer.14731] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 09/27/2021] [Accepted: 10/21/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Medical conditions related to alcohol use disorders (AUD) represent a substantial public health concern. However, only a subset of individuals with AUD develop these conditions and the extent to which genetic and environmental factors that are shared with AUD, versus those distinct from it, contribute to this progression has not yet been determined. METHODS Using data from Swedish national registries for a cohort born from 1932 to 1970 (N = 1,319,214, 48.9% women), we conducted twin-sibling biometric model fitting to examine the genetic and environmental sources of variance that contribute to the liability to alcohol-related medical conditions (AMC). Progression to AMC, determined using medical registry data, was contingent on an AUD registration, which was determined using medical and criminal registry data. RESULTS We identified AUD registrations in 3.2% of women and 9.2% of men. Among individuals with an AUD registration, 14.4% of women and 15.4% of men had an AMC registration. In the final models, we constrained the beta pathway from AUD to AMC and the genetic and unique environmental paths to be equal across sexes. The beta path was estimated at 0.59. AMC was modestly heritable in women (A = 0.32) and men (A = 0.30). The proportion of total heritability unique to AMC was 39.6% among women and 41.3% among men. A higher proportion of total environmental variance was unique to AMC: 76.7% for women and 77.2% for men. In a sensitivity analysis limited to liver-related AMC, we observed similar results, with a slightly lower beta path from AUD to AMC (0.46) and higher proportions of AMC-specific genetic (70.0% in women; 71.7% in men) and environmental (84.5% in both sexes) variance. CONCLUSIONS A moderate-to-substantial proportion of genetic and environmental variance that contributes to AMC risk is not shared with AUD, underscoring the need for additional gene identification efforts for AMC. Furthermore, the prominent influence of environmental factors specific to AMC provides a promising area for the identification of prevention targets. We did not observe significant sex differences in the etiology of AMC, although follow-up is warranted in other well-powered studies.
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Affiliation(s)
- Alexis C. Edwards
- Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, US
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, US
| | | | - Jan Sundquist
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
| | - Kenneth S. Kendler
- Department of Psychiatry, Virginia Commonwealth University School of Medicine, Richmond, VA, US
- Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, US
- Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA, US
| | - Sara Larsson Lönn
- Center for Primary Health Care Research, Lund University, Malmö, Sweden
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Morgan MY, Sharma M, Atkinson SR. Genetic and Environmental Susceptibility to Alcoholic Hepatitis. Clin Liver Dis 2021; 25:517-535. [PMID: 34229837 DOI: 10.1016/j.cld.2021.04.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Constitutional, environmental, and genetic risk factors influence the development of alcohol-related cirrhosis. The amount of alcohol consumed and whether excessive drinking continues after the identification of pre-cirrhotic liver damage are key risk factors. Female sex, ethnicity, obesity, coffee consumption, cigarette smoking, and exposure to other causes of liver injury also influence the risk of disease development. More recently several genetic loci have been robustly associated with the risk for developing significant alcohol-related liver disease. It remains unclear whether additional risk factors are involved in the development of the clinical syndrome of alcoholic hepatitis, but the genetic evidence is suggestive.
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Affiliation(s)
- Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College, Rowland Hill Street, Hampstead, London NW3 2PF, UK.
| | - Moksh Sharma
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College, Rowland Hill Street, Hampstead, London NW3 2PF, UK
| | - Stephen R Atkinson
- Department of Metabolism, Digestion and Reproduction, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
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20
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Seitz HK, Neuman MG. The History of Alcoholic Liver Disease: From an Unrecognized Disease to One of the Most Frequent Diseases in Hepatology. J Clin Med 2021; 10:858. [PMID: 33669694 PMCID: PMC7921942 DOI: 10.3390/jcm10040858] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Revised: 02/10/2021] [Accepted: 02/13/2021] [Indexed: 02/06/2023] Open
Abstract
This review describes the history of alcoholic liver disease from the beginning of the 1950s until now. It details how the hepatotoxicity of alcohol was discovered by epidemiology and basic research primarily by using new feeding techniques in rodents and primates. The article also recognizes the pioneering work of scientists who contributed to the understanding of the pathophysiology of alcoholic liver disease. In addition, clinical aspects, such as the development of diagnostics and treatment options for alcoholic liver disease, are discussed. Up-to-date knowledge of the mechanism of the disease in 2020 is presented.
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Affiliation(s)
- Helmut K. Seitz
- Centre of Liver and Alcohol Diseases, Ethianum Clinic, 69115 Heidelberg, Germany
- Faculty of Medicine, University of Heidelberg, 69117 Heidelberg, Germany
| | - Manuela G. Neuman
- In Vitro Drug Safety and Biotechnology and the Department of Pharmacology and Toxicology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L5, Canada;
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21
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Kwong EK, Puri P. Gut microbiome changes in Nonalcoholic fatty liver disease & alcoholic liver disease. Transl Gastroenterol Hepatol 2021; 6:3. [PMID: 33409398 DOI: 10.21037/tgh.2020.02.18] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Accepted: 02/11/2020] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are some of the most common liver diseases worldwide. The human gut microbiome is dynamic and shifts in bacterial composition have been implicated in many diseases. Studies have shown that there is a shift in bacterial overgrowth favoring pro-inflammatory mediators in patients with advanced disease progression such as cirrhosis. Further investigation demonstrated that the transplantation of gut microbiota from advanced liver disease patients can reproduce severe liver inflammation and injury in mice. Various techniques in manipulating the gut microbiota have been attempted including fecal transplantation and probiotics. This review focuses on the changes in the gut microbiota as well as emerging lines of microbiome work with respect to NAFLD and ALD.
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Affiliation(s)
- Eric K Kwong
- Department of Microbiology and Immunology, McGuire VA Medical Center, Richmond, VA, USA
| | - Puneet Puri
- Section of Gastroenterology, Hepatology and Nutrition, McGuire VA Medical Center, Richmond, VA, USA.,Virginia Commonwealth University, Richmond, VA, USA
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22
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Obesity, Diabetes, Coffee, Tea, and Cannabis Use Alter Risk for Alcohol-Related Cirrhosis in 2 Large Cohorts of High-Risk Drinkers. Am J Gastroenterol 2021; 116:106-115. [PMID: 32868629 DOI: 10.14309/ajg.0000000000000833] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Accepted: 06/17/2020] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Sustained high alcohol intake is necessary but not sufficient to produce alcohol-related cirrhosis. Identification of risk factors, apart from lifetime alcohol exposure, would assist in discovery of mechanisms and prediction of risk. METHODS We conducted a multicenter case-control study (GenomALC) comparing 1,293 cases (with alcohol-related cirrhosis, 75.6% male) and 754 controls (with equivalent alcohol exposure but no evidence of liver disease, 73.6% male). Information confirming or excluding cirrhosis, and on alcohol intake and other potential risk factors, was obtained from clinical records and by interview. Case-control differences in risk factors discovered in the GenomALC participants were validated using similar data from 407 cases and 6,573 controls from UK Biobank. RESULTS The GenomALC case and control groups reported similar lifetime alcohol intake (1,374 vs 1,412 kg). Cases had a higher prevalence of diabetes (20.5% (262/1,288) vs 6.5% (48/734), P = 2.27 × 10-18) and higher premorbid body mass index (26.37 ± 0.16 kg/m2) than controls (24.44 ± 0.18 kg/m2, P = 5.77 × 10-15). Controls were significantly more likely to have been wine drinkers, coffee drinkers, smokers, and cannabis users than cases. Cases reported a higher proportion of parents who died of liver disease than controls (odds ratio 2.25 95% confidence interval 1.55-3.26). Data from UK Biobank confirmed these findings for diabetes, body mass index, proportion of alcohol as wine, and coffee consumption. DISCUSSION If these relationships are causal, measures such as weight loss, intensive treatment of diabetes or prediabetic states, and coffee consumption should reduce the risk of alcohol-related cirrhosis.
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23
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Innes H, Buch S, Hutchinson S, Guha IN, Morling JR, Barnes E, Irving W, Forrest E, Pedergnana V, Goldberg D, Aspinall E, Barclay S, Hayes PC, Dillon J, Nischalke HD, Lutz P, Spengler U, Fischer J, Berg T, Brosch M, Eyer F, Datz C, Mueller S, Peccerella T, Deltenre P, Marot A, Soyka M, McQuillin A, Morgan MY, Hampe J, Stickel F. Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1. Gastroenterology 2020; 159:1276-1289.e7. [PMID: 32561361 DOI: 10.1053/j.gastro.2020.06.014] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2020] [Revised: 05/10/2020] [Accepted: 06/05/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Little is known about genetic factors that affect development of alcohol-related cirrhosis. We performed a genome-wide association study (GWAS) of samples from the United Kingdom Biobank (UKB) to identify polymorphisms associated with risk of alcohol-related liver disease. METHODS We performed a GWAS of 35,839 participants in the UKB with high intake of alcohol against markers of hepatic fibrosis (FIB-4, APRI, and Forns index scores) and hepatocellular injury (levels of aminotransferases). Loci identified in the discovery analysis were tested for their association with alcohol-related cirrhosis in 3 separate European cohorts (phase 1 validation cohort; n=2545). Variants associated with alcohol-related cirrhosis in the validation at a false discovery rate of less than 20% were then directly genotyped in 2 additional European validation cohorts (phase 2 validation, n=2068). RESULTS In the GWAS of the discovery cohort, we identified 50 independent risk loci with genome-wide significance (P < 5 × 10-8). Nine of these loci were significantly associated with alcohol-related cirrhosis in the phase 1 validation cohort; 6 of these 9 loci were significantly associated with alcohol-related cirrhosis in phase 2 validation cohort, at a false discovery rate below 5%. The loci included variants in the mitochondrial amidoxime reducing component 1 gene (MARC1) and the heterogeneous nuclear ribonucleoprotein U like 1 gene (HNRNPUL1). After we adjusted for age, sex, body mass index, and type-2 diabetes in the phase 2 validation cohort, the minor A allele of MARC1:rs2642438 was associated with reduced risk of alcohol-related cirrhosis (adjusted odds ratio, 0.76; P=.0027); conversely, the minor C allele of HNRNPUL1:rs15052 was associated with an increased risk of alcohol-related cirrhosis (adjusted odds ratio, 1.30; P=.020). CONCLUSIONS In a GWAS of samples from the UKB, we identified and validated (in 5 European cohorts) single-nucleotide polymorphisms that affect risk of alcohol-related cirrhosis in opposite directions: the minor A allele in MARC1:rs2642438 decreases risk, whereas the minor C allele in HNRNPUL1:rs15052 increases risk.
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Affiliation(s)
- Hamish Innes
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow United Kingdom; Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom; Health Protection Scotland, Glasgow, United Kingdom.
| | - Stephan Buch
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Germany
| | - Sharon Hutchinson
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow United Kingdom; Health Protection Scotland, Glasgow, United Kingdom
| | - Indra Neil Guha
- National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Joanne R Morling
- Division of Epidemiology and Public Health, University of Nottingham, Nottingham, United Kingdom; National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Eleanor Barnes
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, and the Oxford National Institute for Health Research Biomedical Research Centre, Oxford University, United Kingdom
| | - Will Irving
- National Institute for Health Research Nottingham Biomedical Research Centre, Nottingham University Hospitals National Health Service Trust and the University of Nottingham, Nottingham, United Kingdom
| | - Ewan Forrest
- Glasgow Royal Infirmary, Glasgow, United Kingdom
| | - Vincent Pedergnana
- Laboratoire Maladies Infectieuses et Vecteurs Écologie, Génétique, Évolution et Contrôl (UMR CNRS 5290, UR IRD 224, UM), Montpellier, France
| | - David Goldberg
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow United Kingdom; Health Protection Scotland, Glasgow, United Kingdom
| | - Esther Aspinall
- School of Health and Life Sciences, Glasgow Caledonian University, Glasgow United Kingdom; Health Protection Scotland, Glasgow, United Kingdom
| | | | - Peter C Hayes
- Royal Infirmary Edinburgh, Edinburgh, United Kingdom
| | - John Dillon
- School of Medicine, University of Dundee, Dundee, United Kingdom
| | | | - Philipp Lutz
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Ulrich Spengler
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Janett Fischer
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Thomas Berg
- Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Leipzig, Germany
| | - Mario Brosch
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Germany
| | - Florian Eyer
- Department of Clinical Toxicology, Klinikum Rechts der Isar, Technical University of Munich, Germany
| | - Christian Datz
- Department of Internal Medicine, Hospital Oberndorf, Teaching Hospital of the Paracelsus Private Medical University of Salzburg, Oberndorf, Austria
| | - Sebastian Mueller
- Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany
| | - Teresa Peccerella
- Department of Internal Medicine and Center for Alcohol Research, Salem Medical Center University Hospital Heidelberg, Heidelberg, Germany
| | - Pierre Deltenre
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland
| | - Astrid Marot
- Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Switzerland
| | - Michael Soyka
- Psychiatric hospital, University of Munich, Munich, Germany, and Department of Psychiatry, Meiringen Hospital, Meiringen, Switzerland
| | - Andrew McQuillin
- Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, United Kingdom
| | - Marsha Y Morgan
- Division of Medicine, University College London Institute for Liver & Digestive Health, Royal Free Campus, University College London, London, United Kingdom
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, Technische Universität Dresden, Germany
| | - Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Zurich, Switzerland
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Alcohol-related liver disease: Clinical practice guidelines by the Latin American Association for the Study of the Liver (ALEH). Ann Hepatol 2020; 18:518-535. [PMID: 31053546 DOI: 10.1016/j.aohep.2019.04.005] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2019] [Accepted: 03/06/2019] [Indexed: 02/04/2023]
Abstract
Alcohol-related liver disease (ALD) is a major cause of advanced chronic liver disease in Latin-America, although data on prevalence is limited. Public health policies aimed at reducing the alarming prevalence of alcohol use disorder in Latin-America should be implemented. ALD comprises a clinical-pathological spectrum that ranges from steatosis, steatohepatitis to advanced forms such as alcoholic hepatitis (AH), cirrhosis and hepatocellular carcinoma. Besides genetic factors, the amount of alcohol consumption is the most important risk factor for the development of ALD. Continuous consumption of more than 3 standard drinks per day in men and more than 2 drinks per day in women increases the risk of developing liver disease. The pathogenesis of ALD is only partially understood and recent translational studies have identified novel therapeutic targets. Early forms of ALD are often missed and most clinical attention is focused on AH, which is defined as an abrupt onset of jaundice and liver-related complications. In patients with potential confounding factors, a transjugular biopsy is recommended. The standard therapy for AH (i.e. prednisolone) has not evolved in the last decades yet promising new therapies (i.e. G-CSF, N-acetylcysteine) have been recently proposed. In both patients with early and severe ALD, prolonged abstinence is the most efficient therapeutic measure to decrease long-term morbidity and mortality. A multidisciplinary team including alcohol addiction specialists is recommended to manage patients with ALD. Liver transplantation should be considered in the management of patients with end-stage ALD that do not recover despite abstinence. In selected cases, increasing number of centers are proposing early transplantation for patients with severe AH not responding to medical therapy.
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Abstract
SummaryPart of the familial factor of alcoholism is associated with the existence of genetic vulnerability. Genetic factors which interact with the pathogenesis of alcoholism are nevertheless complex, partial and for the moment partly unknown at the biological level. Recently, many association studies have been published concerning alcohol-dependence and genes coding for the second dopamine receptor. These associations, which have had positive replications, raise many questions. First of all, should the inheritance of alcoholism be regarded as a definitive fact? Secondly what is inherited? It could be alcoholism in general, a component of this disease (for instance, dependence on, sensitivity to or the seeking-process for alcohol), a specific pattern of drinking, presence of complications linked to alcohol abuse, or more general features, common to many addiction diseases. Thirdly, how could dopamine be linked to alcoholism? Furthermore, how should these positive associations be considered, given that two of these studies were negative, and that all linkage studies were negative. Lastly, are there other clues and ways of finding genetic vulnerability factors for alcohol abuse?
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Abstract
SummaryAlcoholic and psychiatric family history were investigated in two groups of alcoholics, recruited differently, and controls. Alcoholics with or without a family history of alcoholism (AFH + and AFH − ) were compared with regard to professional qualifications, personal psychiatric history, age at onset and reasons given for becoming alcoholic. The results can be summarized as follows: the family ‘aggregate’ of alcoholism found was independent of the recruitment. This was not the case for personal psychiatric history for which a gradient was found in the two alcoholic groups. Rates of alcoholism were higher in both the first and second degree relatives. Alcoholics with AFH+ and AFH− differed significantly with regard to inducement by profession, and tended to differ as to age of onset.
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27
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Avila MA, Dufour JF, Gerbes AL, Zoulim F, Bataller R, Burra P, Cortez-Pinto H, Gao B, Gilmore I, Mathurin P, Moreno C, Poznyak V, Schnabl B, Szabo G, Thiele M, Thursz MR. Recent advances in alcohol-related liver disease (ALD): summary of a Gut round table meeting. Gut 2020; 69:764-780. [PMID: 31879281 PMCID: PMC7236084 DOI: 10.1136/gutjnl-2019-319720] [Citation(s) in RCA: 138] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Revised: 11/28/2019] [Accepted: 12/06/2019] [Indexed: 12/14/2022]
Abstract
Alcohol-related liver disease (ALD), which includes a range of disorders of different severity and is one of the most prevalent types of liver disease worldwide, has recently regained increased attention. Among other reasons, the realisation that any alcohol intake, regardless of type of beverage represents a health risk, and the new therapeutic strategies tested in recently published or undergoing clinical trials spur scientific interest in this area.In April 2019, Gut convened a round table panel of experts during the European Association for the Study of the Liver International Liver Congress in Vienna to discuss critical and up-to-date issues and clinical trial data regarding ALD, its epidemiology, diagnosis, management, pathomechanisms, possible future treatments and prevention. This paper summarises the discussion and its conclusions.
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Affiliation(s)
- Matias A Avila
- Hepatology, CIBERehd, IdiSNA, CIMA, University of Navarra, Pamplona, Spain
| | - Jean-François Dufour
- Hepatology, Department of Clinical Research and University Clinic for Visceral Surgery and Medicine, Inselspital, University of Bern, Bern, Switzerland
| | - Alexander L Gerbes
- Liver Centre Munich, Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Fabien Zoulim
- Hepatology Department, INSERM U1052, Hospices Civils de Lyon, Cancer Research Centerl of Lyon, University of Lyon, Lyon, France
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Patrizia Burra
- Multivisceral Transplant Unit, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padua University Hospital, Padua, Italy
| | - Helena Cortez-Pinto
- Departamento de Gastroenterologia, CHLN, Laboratorio de Nutriçao, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, USA
| | - Ian Gilmore
- Liverpool Centre for Alcohol Research, University of Liverpool, Liverpool, UK
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, INSERM U795, Hôpital Huriez, Lille, France
| | - Christophe Moreno
- Service de Gastroentérologie, Hépatopancréatologie et Oncologie Digestive, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
| | - Vladimir Poznyak
- Department of Mental Health and Substance Abuse, World Health Organization, Geneve, Switzerland
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
| | - Gyongyi Szabo
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Maja Thiele
- Department of Gastroenterology and Hepatology, and Department of Clinical Research, Odense University Hospital and University of Southern Denmark, Odense, Denmark
| | - Mark R Thursz
- Department of Metabolism, Faculty of Medicine, Imperial College, London, UK
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28
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Kirpich IA, Warner DR, Feng W, Joshi-Barve S, McClain CJ, Seth D, Zhong W, Zhou Z, Osna NA, Kharbanda KK. Mechanisms, biomarkers and targets for therapy in alcohol-associated liver injury: From Genetics to nutrition: Summary of the ISBRA 2018 symposium. Alcohol 2020; 83:105-114. [PMID: 31129175 PMCID: PMC7043088 DOI: 10.1016/j.alcohol.2019.05.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 05/13/2019] [Accepted: 05/14/2019] [Indexed: 02/06/2023]
Abstract
The symposium "Mechanisms, Biomarkers and Targets for Therapy in Alcohol-associated Liver Injury: From Genetics to Nutrition" was held at the 19th Congress of International Society for Biomedical Research on Alcoholism on September 13th, 2018 in Kyoto, Japan. The goal of the symposium was to discuss the importance of genetics and nutrition in alcoholic liver disease (ALD) development from mechanistic and therapeutic perspectives. The following is a summary of this session addressing the gene polymorphisms in ALD, the role of zinc in gut-liver axis perturbations associated with ALD, highlighting the importance of dietary fat in ALD pathogenesis, the hepatic n6 and n3 PUFA oxylipin pattern associated with ethanol-induced liver injury, and finally deliberating on new biomarkers for alcoholic hepatitis and their implications for diagnosis and therapy. This summary of the symposium will benefit junior and senior faculty currently investigating alcohol-induced organ pathology as well as undergraduate, graduate, and post-graduate students and fellows.
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Affiliation(s)
- Irina A Kirpich
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Dennis R Warner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA
| | - Wenke Feng
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Swati Joshi-Barve
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Craig J McClain
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, University of Louisville, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY, USA; University of Louisville Alcohol Center, University of Louisville School of Medicine, Louisville, KY, USA; Robley Rex Veterans Medical Center, Louisville, KY, USA; Hepatobiology & Toxicology Program, University of Louisville, Louisville, KY, USA
| | - Devanshi Seth
- Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia, And Centenary Institute of Cancer Medicine and Cell Biology, The University of Sydney, Sydney, NSW, Australia
| | - Wei Zhong
- Center for Translational Biomedical Research, Department of Nutrition, University of North Carolina at Greensboro, Kannapolis, NC, 28081, USA
| | - Zhanxiang Zhou
- Center for Translational Biomedical Research, Department of Nutrition, University of North Carolina at Greensboro, Kannapolis, NC, 28081, USA
| | - Natalia A Osna
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA
| | - Kusum K Kharbanda
- Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA; Department of Biochemistry & Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
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29
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Bataller R, Cabezas J, Aller R, Ventura-Cots M, Abad J, Albillos A, Altamirano J, Arias-Loste MT, Bañares R, Caballería J, Caballería L, Carrión JA, Diago M, Fernández Rodríguez C, Gallego R, García-Cortes M, García-Monzón C, Genescà J, Ginés P, Hernandez-Guerra M, Jorquera F, Lligoña A, Molina E, Pareja MJ, Planas R, Tomé S, Salmerón J, Romero-Gómez M. Alcohol-related liver disease. Clinical practice guidelines. Consensus document sponsored by AEEH. GASTROENTEROLOGIA Y HEPATOLOGIA 2019; 42:657-676. [PMID: 31771785 DOI: 10.1016/j.gastrohep.2019.09.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2019] [Accepted: 09/02/2019] [Indexed: 02/07/2023]
Abstract
Alcohol-related liver disease (ARLD) is the most prevalent cause of advanced liver disease and liver cirrhosis in Europe, including Spain. According to the World Health Organization the fraction of liver cirrhosis attributable to alcohol use in Spain is 73.8% among men and 56.3% among women. ARLD includes various stages such as steatohepatitis, cirrhosis and hepatocellular cancer. In addition, patients with underlying ARLD and heavy alcohol intake may develop alcoholic hepatitis, which is associated with high mortality. To date, the only effective treatment to treat ARLD is prolonged withdrawal. There are no specific treatments, and the only treatment that increases life expectancy in alcoholic hepatitis is prednisolone. For patients with alcoholic hepatitis who do not respond to treatment, some centres offer the possibility of an early transplant. These clinical practice guidelines aim to propose recommendations on ARLD taking into account their relevance as a cause of advanced chronic liver disease and liver cirrhosis in our setting. This paper aims to answer the key questions for the clinical practice of Gastroenterology, Hepatology, as well as Internal Medicine and Primary Health Centres, making the most up-to-date information regarding the management and treatment of ARLD available to health professionals. These guidelines provide evidence-based recommendations for the clinical management of this disease.
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Affiliation(s)
- Ramón Bataller
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, Estados Unidos.
| | - Joaquín Cabezas
- Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Instituto de investigación Sanitaria Valdecilla (IDIVAL), Santander, Cantabria, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España
| | - Rocío Aller
- Servicio de Gastroenterología, Hospital Clínico Universitario de Valladolid, Valladolid, España; Facultad de Medicina, Universidad de Valladolid, Valladolid, España; Centro de Investigación de Endocrinología y Nutrición, Facultad de Medicina de Valladolid, Valladolid, España
| | - Meritxell Ventura-Cots
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Center for Liver Diseases, University of Pittsburgh Medical Center, Pittsburgh, PA, Estados Unidos; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España
| | - Javier Abad
- Servicio de Gastroenterología y Hepatología, Hospital Puerta de Hierro, Madrid, España
| | - Agustín Albillos
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Servicio de Gastroenterología y Hepatología, Hospital Universitario Ramón y Cajal, Universidad de Alcalá, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Madrid, España
| | - José Altamirano
- Deparmento de Medicina Interna, Hospital Quironsalud, Barcelona, España
| | - María Teresa Arias-Loste
- Servicio de Aparato Digestivo, Hospital Universitario Marqués de Valdecilla, Instituto de investigación Sanitaria Valdecilla (IDIVAL), Santander, Cantabria, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España
| | - Rafael Bañares
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Servicio de Gastroenterología y Hepatología, Hospital Gregorio Marañón, Madrid, España
| | - Juan Caballería
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Unidad de Hepatología, Hospital Clínic, IDIBAPS, Barcelona, España
| | - Llorenç Caballería
- Unidad de Apoyo a la Investigación de la Atención Primaria en la Metropolitana Norte, Barcelona, España
| | | | - Moisés Diago
- Servicio de Aparato Digestivo, Hospital General de Valencia, Valencia, España
| | - Conrado Fernández Rodríguez
- Servicio de Gastroenterología, Hospital Universitario Fundación Alcorcón. Facultad de Medicina, Universidad Rey Juan Carlos, Alcorcón, Madrid, España
| | - Rocío Gallego
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; UGC Aparato Digestivo, Instituto de Biomedicina de Sevilla. Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, España
| | | | | | - Joan Genescà
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Servicio de Medicina Interna-Hepatología, Hospital Universitario Vall d'Hebron, Institut de Recerca Vall d'Hebron (VHIR), Universitat Autònoma de Barcelona, Barcelona, España
| | - Pere Ginés
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Unidad de Apoyo a la Investigación de la Atención Primaria en la Metropolitana Norte, Barcelona, España
| | | | - Francisco Jorquera
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Servicio de Aparato Digestivo, Complejo Asistencial Universitario de León, IBIOMED, León, España
| | - Anna Lligoña
- Unidad de Alcohologia, Departamento de Psiquiatría, Hospital Clínic. Barcelona, España
| | - Esther Molina
- Unidad de Hepatología, Servicio de Aparato Digestivo, Hospital Clínico-Xerencia de Xestión Integrada de Santiago de Compostela, Santiago de Compostela, La Coruña, España
| | | | - Ramón Planas
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; Departamento de Hepatología, Hospital Germans Trias i Pujol, Badalona, Barcelona, España
| | - Santiago Tomé
- Unidad de Trasplante Hepático, Hospital Clínico Universitario, Santiago de Compostela, La Coruña, España
| | - Javier Salmerón
- UGC de Aparato Digestivo, Hospital San Cecilio, Granada, España
| | - Manuel Romero-Gómez
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España; UGC Aparato Digestivo, Instituto de Biomedicina de Sevilla. Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Sevilla, España
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30
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Kwong EK, Liu R, Zhao D, Li X, Zhu W, Wang X, Gurley EC, Lai G, Liu J, Hylemon PB, Zhou H. The role of sphingosine kinase 2 in alcoholic liver disease. Dig Liver Dis 2019; 51:1154-1163. [PMID: 31003959 PMCID: PMC6682426 DOI: 10.1016/j.dld.2019.03.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2019] [Revised: 03/18/2019] [Accepted: 03/19/2019] [Indexed: 02/08/2023]
Abstract
Alcoholic liver disease (ALD) is one of the most common liver diseases worldwide. However, the exact mechanisms underlying ALD remain unclear. Previous studies reported that sphingosine kinase 2 (SphK2) plays an essential role in regulating hepatic lipid metabolism. In the current study, we demonstrate that compared to wild-type (WT) mice, SphK2 deficient (SphK2-/-) mice exhibited a greater degree of liver injury and hepatic lipid accumulation after feeding with an alcohol diet for 60 days. This is accompanied by a down-regulation of steroid 7-alpha-hydroxylase (Cyp7b1) and an up-regulation of pro-inflammatory mediators (Tnfα, F4/80, Il-1β). In vitro experiments showed that alcohol induced SphK2 expression in mouse primary hepatocytes and cultured mouse macrophages. Furthermore, alcohol feeding induced a more severe intestinal barrier dysfunction in SphK2-/- mice than WT mice. Deficiency of SphK2 impaired the growth of intestinal organoids. Finally, SphK2 expression levels were down-regulated in the livers of human patients with alcoholic cirrhosis and hepatocellular carcinoma compared to healthy controls. In summary, these findings suggest that SphK2 is a crucial regulator of hepatic lipid metabolism and that modulating the SphK2-mediated signaling pathway may represent a novel therapeutic strategy for the treatment of ALD and other metabolic liver diseases.
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Affiliation(s)
- Eric K. Kwong
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Runping Liu
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Derrick Zhao
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Xiaojiaoyang Li
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Weiwei Zhu
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Xuan Wang
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Emily C. Gurley
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Guanhua Lai
- Department of Pathology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Jimin Liu
- Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada
| | - Phillip B. Hylemon
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Huiping Zhou
- Department of Microbiology and Immunology, Medical College of Virginia and McGuire Veterans Affairs Medical Center, Virginia Commonwealth University, Richmond, Virginia, USA
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31
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Hosseini N, Shor J, Szabo G. Alcoholic Hepatitis: A Review. Alcohol Alcohol 2019; 54:408-416. [PMID: 31219169 PMCID: PMC6671387 DOI: 10.1093/alcalc/agz036] [Citation(s) in RCA: 109] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 04/05/2019] [Accepted: 04/09/2019] [Indexed: 12/16/2022] Open
Abstract
Alcoholic liver disease (ALD) represents a spectrum of injury, ranging from simple steatosis to alcoholic hepatitis to cirrhosis. Regular alcohol use results in fatty changes in the liver which can develop into inflammation, fibrosis and ultimately cirrhosis with continued, excessive drinking. Alcoholic hepatitis (AH) is an acute hepatic inflammation associated with significant morbidity and mortality that can occur in patients with steatosis or underlying cirrhosis. The pathogenesis of ALD is multifactorial and in addition to genetic factors, alcohol-induced hepatocyte damage, reactive oxygen species, gut-derived microbial components result in steatosis and inflammatory cell (macrophage and neutrophil leukocyte) recruitment and activation in the liver. Continued alcohol and pro-inflammatory cytokines induce stellate cell activation and result in progressive fibrosis. Other than cessation of alcohol use, medical therapy of AH is limited to prednisolone in a subset of patients. Given the high mortality of AH and the progressive nature of ALD, there is a major need for new therapeutic intervention for this underserved patient population.
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Affiliation(s)
- Nooshin Hosseini
- University of Massachusetts, Gastroenterology, University of Massachusetts Medical School
| | - Julia Shor
- University of Massachusetts, Gastroenterology, University of Massachusetts Medical School
| | - Gyongyi Szabo
- Professor, Department of Medicine, University of Massachusetts, 364 Plantation Street, LRB-208, Worcester, MA, USA
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Meroni M, Longo M, Rametta R, Dongiovanni P. Genetic and Epigenetic Modifiers of Alcoholic Liver Disease. Int J Mol Sci 2018; 19:E3857. [PMID: 30513996 PMCID: PMC6320903 DOI: 10.3390/ijms19123857] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2018] [Revised: 10/31/2018] [Accepted: 11/28/2018] [Indexed: 12/12/2022] Open
Abstract
Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.
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Affiliation(s)
- Marica Meroni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Miriam Longo
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Raffaela Rametta
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Pad. Granelli, via F Sforza 35, 20122 Milan, Italy.
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33
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Nguyen-Khac E, Dejour V, Sarba R, Yzet T, Turpin J, Chatelain D, Marcq I, Chivot C, Maizel J, Papillon C, Attencourt C, Houchi H. Hépatite alcoolique aiguë sévère. MEDECINE INTENSIVE REANIMATION 2018. [DOI: 10.3166/rea-2018-0069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Tout patient consommateur chronique et excessif d’alcool avec un ictère récent doit être évalué par le score de Maddrey à la recherche d’une hépatite alcoolique aiguë sévère. Les corticostéroïdes représentent le traitement de première ligne, associés à un soutien nutritionnel adapté et à une abstinence alcoolique. La combinaison corticostéroïdes plus N-acétylcystéine (perfusée pendant les cinq premiers jours) améliore la survie à court terme par rapport aux corticostéroïdes seuls, constituant une option thérapeutique de première ligne. La réponse au traitement est évaluée au septième jour par le modèle de Lille inférieur ou égal à 0,45. Le pronostic des patients non répondeurs aux corticostéroïdes avec un modèle de Lille supérieur à 0,45 est sombre avec une survie de 23 % à six mois. Pour des patients non répondeurs aux corticostéroïdes et sélectionnés, la transplantation hépatique précoce améliore significativement la survie à six mois et à long terme.
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34
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Wen CS, Ho CM. Alcohol or Not: A Review Comparing Initial Mechanisms, Contributing Factors, and Liver Transplantation Outcomes Between Alcoholic and Nonalcoholic Steatohepatitis. EUROPEAN MEDICAL JOURNAL 2018. [DOI: 10.33590/emj/10310116] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Chronic liver diseases take many forms; alcohol-related liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are two common illnesses that potentially lead to cirrhosis, liver failure, and liver cancer. It is estimated that a quarter of heavy drinkers develop ALD and the same portion of people without heavy drinking habits have NAFLD. Alcohol intake is regularly used to differentiate NAFLD from ALD; however, diagnosis based on the discrimination threshold may be suboptimal when facing an obese patient with a high level of alcohol exposure. Therefore, understanding the common and/or different mechanism(s) driving each disease is extremely important. The ‘two-hit’ or ‘multi-hit’ hypothesis is used to explain the pathogenesis of both diseases. The ‘first hit’ refers to developing steatosis, the accumulation of fat components in the liver, and the ‘second hits’ are factors leading to oxidative stress, inflammation, and fibrosis, such as metabolic syndromes (e.g., morbid obesity, hyperglycaemia, hyperlipidaemia, disturbed circadian cycles, and altered intestinal microbiota) and environmental toxins (e.g., cigarette smoke and pollutants). Heritable factors also affect the probability and disease progression of both ALD and NAFLD. Whereas PNPLA3 and TM6SF2 variants are influential genetic risk factors for the diseases, epigenetic factors, such as DNA methylation, post-translational histone modifications, and small non-coding RNA, are of paramount importance. Moreover, considering that both ALD and NAFLD patients may eventually develop end-stage liver disease and require liver transplantation, the authors extensively investigated the worldwide outcomes from original literature for these two aetiologies, and the results showed no obvious differences in post-transplantation survival between them. Precise percentage determination of these two aetiologies contributing to steatohepatitis and its secondary injuries in the future would allow for better strategies for therapeutic and preventive intervention.
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Seitz HK, Bataller R, Cortez-Pinto H, Gao B, Gual A, Lackner C, Mathurin P, Mueller S, Szabo G, Tsukamoto H. Alcoholic liver disease. Nat Rev Dis Primers 2018; 4:16. [PMID: 30115921 DOI: 10.1038/s41572-018-0014-7] [Citation(s) in RCA: 756] [Impact Index Per Article: 108.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Alcoholic liver disease (ALD) is the most prevalent type of chronic liver disease worldwide. ALD can progress from alcoholic fatty liver (AFL) to alcoholic steatohepatitis (ASH), which is characterized by hepatic inflammation. Chronic ASH can eventually lead to fibrosis and cirrhosis and in some cases hepatocellular cancer (HCC). In addition, severe ASH (with or without cirrhosis) can lead to alcoholic hepatitis, which is an acute clinical presentation of ALD that is associated with liver failure and high mortality. Most individuals consuming >40 g of alcohol per day develop AFL; however, only a subset of individuals will develop more advanced disease. Genetic, epigenetic and non-genetic factors might explain the considerable interindividual variation in ALD phenotype. The pathogenesis of ALD includes hepatic steatosis, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation. Diagnosis of ALD involves assessing patients for alcohol use disorder and signs of advanced liver disease. The degree of AFL and liver fibrosis can be determined by ultrasonography, transient elastography, MRI, measurement of serum biomarkers and liver biopsy histology. Alcohol abstinence achieved by psychosomatic intervention is the best treatment for all stages of ALD. In the case of advanced disease such as cirrhosis or HCC, liver transplantation may be required. Thus, new therapies are urgently needed.
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Affiliation(s)
- Helmut K Seitz
- Centre of Alcohol Research (CAR),, University of Heidelberg, Heidelberg and Department of Medicine, Salem Medical Center, Heidelberg, Germany.
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA, USA
| | - Helena Cortez-Pinto
- Departmento de Gastroenterologia, CHLN, Laboratorio de Nutricão, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Bin Gao
- Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, NIH, Bethesda, MD, USA
| | - Antoni Gual
- Addiction Unit, Neuroscience Institute Hospital Clinic, IDIBAPS, Barcelona, Spain
| | - Carolin Lackner
- Institute of Pathology, Medical University of Graz, Graz, Austria
| | - Philippe Mathurin
- Service des Maladies de l'Appareil Digestif, Universite Lille 2 and INSERM U795, Lille, France
| | - Sebastian Mueller
- Centre of Alcohol Research (CAR),, University of Heidelberg, Heidelberg and Department of Medicine, Salem Medical Center, Heidelberg, Germany
| | - Gyongyi Szabo
- Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Hidekazu Tsukamoto
- University of Southern California Keck School of Medicine and Greater Los Angeles VA Healthcare System, Los Angeles, CA, USA
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Nguyen-Khac E, Dejour V, Sarba R, Yzet T, Chatelain D, Marcq I, Chivot C, Papillon CA, Attencourt C, Houchi H. Hépatite alcoolique aiguë sévère. Presse Med 2018; 47:655-666. [DOI: 10.1016/j.lpm.2018.05.013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Thursz M, Gual A, Lackner C, Mathurin P, Moreno C, Spahr L, Sterneck M, Cortez-Pinto H. EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. J Hepatol 2018; 69:154-181. [PMID: 29628280 DOI: 10.1016/j.jhep.2018.03.018] [Citation(s) in RCA: 563] [Impact Index Per Article: 80.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Accepted: 03/20/2018] [Indexed: 12/12/2022]
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Abstract
Alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD) are leading causes of chronic liver disease globally. Both ARLD and NAFLD are multifactorial and refer to a spectrum of disease severity, ranging from steatosis through steatohepatitis to fibrosis and cirrhosis. Both diseases exhibit substantial inter-patient variation in long-term outcomes and are best considered complex disease traits where genetic and environmental factors interact to mediate disease severity and progression. Here, we briefly review the current literature describing the best validated genetic modifiers that influence severity of these liver conditions, including variants of the genes PNPLA3, TM6SF2 and MBOAT7, which have also been implicated in lipid dysregulation.
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Affiliation(s)
- Emma Scott
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
| | - Quentin M Anstee
- Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK
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Singal AK, Bataller R, Ahn J, Kamath PS, Shah VH. ACG Clinical Guideline: Alcoholic Liver Disease. Am J Gastroenterol 2018; 113:175-194. [PMID: 29336434 PMCID: PMC6524956 DOI: 10.1038/ajg.2017.469] [Citation(s) in RCA: 543] [Impact Index Per Article: 77.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 11/08/2017] [Indexed: 02/07/2023]
Abstract
Alcoholic liver disease (ALD) comprises a clinical-histologic spectrum including fatty liver, alcoholic hepatitis (AH), and cirrhosis with its complications. Most patients are diagnosed at advanced stages and data on the prevalence and profile of patients with early disease are limited. Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Prolonged abstinence is the most effective strategy to prevent disease progression. AH presents with rapid onset or worsening of jaundice, and in severe cases may transition to acute on chronic liver failure when the risk for mortality, depending on the number of extra-hepatic organ failures, may be as high as 20-50% at 1 month. Corticosteroids provide short-term survival benefit in about half of treated patients with severe AH and long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. General measures in patients hospitalized with ALD include inpatient management of liver disease complications, management of alcohol withdrawal syndrome, surveillance for infections and early effective antibiotic therapy, nutritional supplementation, and treatment of the underlying alcohol-use disorder. Liver transplantation, a definitive treatment option in patients with advanced alcoholic cirrhosis, may also be considered in selected patients with AH cases, who do not respond to medical therapy. There is a clinical unmet need to develop more effective and safer therapies for patients with ALD.
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Affiliation(s)
- Ashwani K. Singal
- Division of Gastroenterology and Hepatology, University of Alabama at Birmingham School of Medicine , Birmingham , Alabama , USA
| | - Ramon Bataller
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Liver Research Center , Pittsburgh , Pennsylvania , USA
| | - Joseph Ahn
- Division of Gastroenterology and Hepatology, Oregon Health and Science University , Portland , Oregon , USA
| | - Patrick S. Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester , Minnesota ,USA
| | - Vijay H. Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic , Rochester , Minnesota ,USA
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Rausch V, Mueller S. Suppressed Fat Mobilization Due to PNPLA3 rs738409 -Associated Liver Damage in Heavy Drinkers: The Liver Damage Feedback Hypothesis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1032:153-172. [PMID: 30362098 DOI: 10.1007/978-3-319-98788-0_12] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
PNPLA3 variant rs738409 has been identified as important progression factor in patients with ALD and NAFLD, the most common liver diseases worldwide. These findings point towards similarities between metabolism of alcohol and fat with regard to the PNPLA3 gene. However, despite many efforts, neither the mechanisms of PNPLA3-related liver damage nor the physiological role of PNPLA3 are fully understood. Based on a large monocentric cohort of Caucasian heavy drinkers we could recently provide evidence that PNPLA3 GG primarily correlated with signs of liver damage (steatohepatitis, ballooning) but less with steatosis. Moreover, upon alcohol withdrawal, PNPLA3 GG carriers showed a delayed inflammation-associated resolution of liver stiffness. In line with the histological findings, hepatic fat content as quantified by CAP (controlled attenuation parameter) did not depend on PNPLA3 status and decreased equally in all genotypes by ca. 30 dB/m during alcohol withdrawal. Preliminary additional analysis from this large cohort indicates that PNPLA3 GG carriers (8.2%) drink significantly less high percentage beverages (23% vs 55%, p < 0.001) but show no metabolic phenotype such as increased weight, BMI or diabetes. On the molecular level, key molecules, important for lipolysis and flow of free fatty acids to the liver were drastically reduced in G carriers. These included the liver-synthesized serum ApoA1, the LD-associated protein perilipin5 and the recently identified hepato-protective transcriptional cofactor transducin beta-like-related 1 (TBLR1). Based on these findings, we here introduce the liver damage feedback hypothesis. Accordingly, PNPLA3-mediated liver damage (e.g. by enhanced metabolic activity) suppresses the mobilization of fat towards the liver at various levels (reduced serum lipid flux to the liver and fat mobilization from peripheric adipose tissues, suppressed hepatocyte fat release and avoidance of high percentage alcohol beverages). Finally, the liver damage feedback hypothesis identifies a novel and central role of liver damage on systemic fat homeostasis, which has not been appreciated so far.
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Affiliation(s)
- Vanessa Rausch
- Center for Alcohol Research, University Hospital Heidelberg and Salem Medical Center, Heidelberg, Germany.
| | - Sebastian Mueller
- Department of Internal Medicine, Salem Medical Center and Center for Alcohol Research, University of Heidelberg, Heidelberg, Germany
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Burton R, Henn C, Lavoie D, O'Connor R, Perkins C, Sweeney K, Greaves F, Ferguson B, Beynon C, Belloni A, Musto V, Marsden J, Sheron N. A rapid evidence review of the effectiveness and cost-effectiveness of alcohol control policies: an English perspective. Lancet 2017; 389:1558-1580. [PMID: 27919442 DOI: 10.1016/s0140-6736(16)32420-5] [Citation(s) in RCA: 215] [Impact Index Per Article: 26.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2016] [Revised: 11/14/2016] [Accepted: 11/16/2016] [Indexed: 02/09/2023]
Abstract
This paper reviews the evidence for the effectiveness and cost-effectiveness of policies to reduce alcohol-related harm. Policies focus on price, marketing, availability, information and education, the drinking environment, drink-driving, and brief interventions and treatment. Although there is variability in research design and measured outcomes, evidence supports the effectiveness and cost-effectiveness of policies that address affordability and marketing. An adequate reduction in temporal availability, particularly late night on-sale availability, is effective and cost-effective. Individually-directed interventions delivered to at-risk drinkers and enforced legislative measures are also effective. Providing information and education increases awareness, but is not sufficient to produce long-lasting changes in behaviour. At best, interventions enacted in and around the drinking environment lead to small reductions in acute alcohol-related harm. Overall, there is a rich evidence base to support the decisions of policy makers in implementing the most effective and cost-effective policies to reduce alcohol-related harm.
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Affiliation(s)
- Robyn Burton
- Public Health England, London, UK; Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | | | | | | | | | | | - Felix Greaves
- Public Health England, London, UK; Department of Primary Care and Public Health, Imperial College London, London, UK
| | - Brian Ferguson
- Public Health England, London, UK; Department of Health Sciences, University of York, York, UK
| | | | | | | | - John Marsden
- Public Health England, London, UK; Addictions Department, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK
| | - Nick Sheron
- Public Health England, London, UK; Faculty of Medicine, University of Southampton, Southampton, UK
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Herta T, Fischer J, Berg T. Genetik metabolischer und viraler Lebererkrankungen. DER GASTROENTEROLOGE 2017; 12:16-31. [DOI: 10.1007/s11377-016-0128-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Reilly MT, Noronha A, Goldman D, Koob GF. Genetic studies of alcohol dependence in the context of the addiction cycle. Neuropharmacology 2017; 122:3-21. [PMID: 28118990 DOI: 10.1016/j.neuropharm.2017.01.017] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 01/13/2017] [Accepted: 01/19/2017] [Indexed: 12/16/2022]
Abstract
Family, twin and adoption studies demonstrate clearly that alcohol dependence and alcohol use disorders are phenotypically complex and heritable. The heritability of alcohol use disorders is estimated at approximately 50-60% of the total phenotypic variability. Vulnerability to alcohol use disorders can be due to multiple genetic or environmental factors or their interaction which gives rise to extensive and daunting heterogeneity. This heterogeneity makes it a significant challenge in mapping and identifying the specific genes that influence alcohol use disorders. Genetic linkage and (candidate gene) association studies have been used now for decades to map and characterize genomic loci and genes that underlie the genetic vulnerability to alcohol use disorders. These approaches have been moderately successful in identifying several genes that contribute to the complexity of alcohol use disorders. Recently, genome-wide association studies have become one of the major tools for identifying genes for alcohol use disorders by examining correlations between millions of common single-nucleotide polymorphisms with diagnosis status. Genome-wide association studies are just beginning to uncover novel biology; however, the functional significance of results remains a matter of extensive debate and uncertainty. In this review, we present a select group of genome-wide association studies of alcohol dependence, as one example of a way to generate functional hypotheses, within the addiction cycle framework. This analysis may provide novel directions for validating the functional significance of alcohol dependence candidate genes. This article is part of the Special Issue entitled "Alcoholism".
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Affiliation(s)
- Matthew T Reilly
- National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Division of Neuroscience and Behavior, 5635 Fishers Lane, Bethesda, MD 20852, USA.
| | - Antonio Noronha
- National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Division of Neuroscience and Behavior, 5635 Fishers Lane, Bethesda, MD 20852, USA
| | - David Goldman
- National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Chief, Laboratory of Neurogenetics, 5635 Fishers Lane, Bethesda, MD 20852, USA
| | - George F Koob
- National Institutes of Health (NIH), National Institute on Alcohol Abuse and Alcoholism (NIAAA), Director NIAAA, 5635 Fishers Lane, Bethesda, MD 20852, USA
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Stickel F, Moreno C, Hampe J, Morgan MY. The genetics of alcohol dependence and alcohol-related liver disease. J Hepatol 2017; 66:195-211. [PMID: 27575312 DOI: 10.1016/j.jhep.2016.08.011] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2016] [Revised: 08/15/2016] [Accepted: 08/16/2016] [Indexed: 12/19/2022]
Abstract
The susceptibility to developing alcohol dependence and significant alcohol-related liver injury is determined by a number of constitutional, environmental and genetic factors, although the nature and level of interplay between them remains unclear. The familiality and heritability of alcohol dependence is well-documented but, to date, no strong candidate genes conferring increased risk have emerged, although variants in alcohol dehydrogenase and acetaldehyde dehydrogenase have been shown to confer protection, predominantly in individuals of East Asian ancestry. Population contamination with confounders such as drug co-dependence and psychiatric and physical co-morbidity may explain the essentially negative genome-wide association studies in this disorder. The familiality and hereditability of alcohol-related cirrhosis is not as well-documented but three strong candidate genes PNPLA3, TM6SF2 and MBOAT7, have been identified. The mechanisms by which variants in these genes confer risk and the nature of the functional interplay between them remains to be determined but, when elucidated, will undoubtedly increase our understanding of the pathophysiology of this disease. The way in which this genetic information could potentially inform patient management has yet to be determined and tested.
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Affiliation(s)
- Felix Stickel
- Department of Gastroenterology and Hepatology, University Hospital of Zurich, Switzerland.
| | - Christophe Moreno
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Jochen Hampe
- Medical Department 1, University Hospital Dresden, TU Dresden, Germany
| | - Marsha Y Morgan
- UCL Institute for Liver & Digestive Health, Division of Medicine, Royal Free Campus, University College London, UK
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Rausch V, Peccerella T, Lackner C, Yagmur E, Seitz HK, Longerich T, Mueller S. Primary liver injury and delayed resolution of liver stiffness after alcohol detoxification in heavy drinkers with the PNPLA3 variant I148M. World J Hepatol 2016; 8:1547-1556. [PMID: 28050235 PMCID: PMC5165268 DOI: 10.4254/wjh.v8.i35.1547] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2016] [Revised: 07/15/2016] [Accepted: 09/18/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the influence of PNPLA3 genotype in heavy drinkers on serum markers and liver stiffness (LS) during alcohol withdrawal and its association with histology.
METHODS Caucasian heavy drinkers (n = 521) with a mean alcohol consumption of 192.1 g/d (median alcohol consumption: 169.0 g/d; 95%CI: 179.0-203.3) were enrolled at the Salem Medical Center, University of Heidelberg. LS was measured by transient elastography (Fibroscan, Echosens SA, Paris, France). LS and serum markers were prospectively studied in these patients with all stages of alcoholic liver disease (steatosis, steatohepatitis, fibrosis) prior and after alcohol detoxification with a mean observation interval of 6.2 ± 3.2 d. A liver biopsy with histological analysis including the Kleiner score was obtained in 80 patients.
RESULTS The PNPLA3 rs738409 genotype distribution for CC, CG and GG was 39.2%, 52.6% and 8.2%. GG genotype primarily correlated with histological steatohepatitis (r = 0.404, P < 0.005), ballooning (r = 0.319, P < 0.005) and less with steatosis (r = 0.264, P < 0.05). Mean LS was lowest in CC carriers (13.1 kPa) as compared to CG and GG carriers (17.6 and 17.2 kPa). Notably, LS primarily correlated with fibrosis stage (r = 0.828, P < 0.005), ballooning (r = 0.516, P < 0.005), steatohepatitis (r = 0.319, P < 0.005) but not with steatosis. After alcohol withdrawal, LS did not change in CC carriers, significantly decreased in CG-carriers from 17.6 to 12.7 kPa but to a lesser extent in GG carriers from 17.6 to 14.5 kPa. This was due to prolonged resolution of inflammation with significantly elevated aspartate transaminase levels after alcohol withdrawal in GG carriers. Non-invasive fibrosis assessment by LS in all patients showed a significantly higher F0 rate as compared to the biopsy cohort (47% vs 6%) with 3.8% more CC carriers while 3.7% less were seen in the F4 cirrhosis group. Thus, about 20% of patients with alcoholic liver cirrhosis would be attributable to PNPLA3 G variants. The OR to develop cirrhosis corrected for age, gender and body mass index was 1.295 (95%CI: 0.787-2.131) for CG + GG carriers.
CONCLUSION In heavy drinkers, PNPLA3 GG primarily correlates with ballooning/steatohepatitis but not steatosis resulting in a delayed inflammation-associated resolution of LS. Consequently, sustained ballooning-associated LS elevation seems to be a potential risk factor for fibrosis progression in PNPLA3 GG carriers.
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Abstract
Alcoholic hepatitis is an acute form of alcoholic liver disease with variable severity that develops in patients who usually have a history of prolonged and recent alcohol abuse. The diagnosis is clinical and depends on history, physical examination, and laboratory derangements. Liver biopsy is diagnostic but not universally performed, and noninvasive diagnostic modalities are under development. Scoring systems are used to assess severity of disease, predict mortality, and guide decisions for initiation of specific therapies. The natural history and long-term outcomes of alcoholic hepatitis, including recurrence, progression to cirrhosis, and mortality, vary and depend partly on abstinence from alcohol use.
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Affiliation(s)
- Mohannad F. Dugum
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Arthur J. McCullough
- Department of Gastroenterology and Pathobiology, Digestive Disease Institute, Cleveland Clinic, Cleveland, Ohio
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Abstract
Drug addiction and addictions to foods, sex, gambling, exercise, and many other things are widespread in modern societies. Addiction or dependence are terms used to describe persistent psychoactive drug use, but these terms also can be applied to other forms of repetitive behaviors. Many of these repetitive behaviors are regulated by specific regions of the brain that are influenced by drugs. Consequently, drug addiction may involve effects on systems that are involved in regulating forms of addiction that are necessary for the maintenance of life. Addictions also seem to be regulated by genetic factors. Because drug addiction may influence the activities of systems that evolved to regulate behaviors necessary to survive (ie, eating and drinking) and because individuals may differ in addict-ability for a given drug caused by genetic reasons, addiction should be considered as a disease and therapy should be developed with this concept in mind.
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Affiliation(s)
- Allan C. Collins
- Institute for Behavioral Genetics, Department of Psychology; and School of Pharmacy, University of Colorado, Boulder, CO
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Anstee QM, Seth D, Day CP. Genetic Factors That Affect Risk of Alcoholic and Nonalcoholic Fatty Liver Disease. Gastroenterology 2016; 150:1728-1744.e7. [PMID: 26873399 DOI: 10.1053/j.gastro.2016.01.037] [Citation(s) in RCA: 175] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Revised: 01/17/2016] [Accepted: 01/20/2016] [Indexed: 02/07/2023]
Abstract
Genome-wide association studies and candidate gene studies have informed our understanding of factors contributing to the well-recognized interindividual variation in the progression and outcomes of alcoholic liver disease and nonalcoholic fatty liver disease. We discuss the mounting evidence for shared modifiers and common pathophysiological processes that contribute to development of both diseases. We discuss the functions of proteins encoded by risk variants of genes including patatin-like phospholipase domain-containing 3 and transmembrane 6 superfamily member 2, as well as epigenetic factors that contribute to the pathogenesis of alcoholic liver disease and nonalcoholic fatty liver disease. We also discuss important areas of future genetic research and their potential to affect clinical management of patients.
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Affiliation(s)
- Quentin M Anstee
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom.
| | - Devanshi Seth
- Centenary Institute of Cancer Medicine, Royal Prince Alfred Hospital, Camperdown, Australia; Drug Health Services, Royal Prince Alfred Hospital, Camperdown, Australia; Central Clinical School, The University of Sydney, Camperdown, Australia
| | - Christopher P Day
- Liver Research Group, Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle-upon-Tyne, United Kingdom
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Whitfield JB, Rahman K, Haber PS, Day CP, Masson S, Daly AK, Cordell HJ, Mueller S, Seitz HK, Liangpunsakul S, Westerhold C, Liang T, Lumeng L, Foroud T, Nalpas B, Mathurin P, Stickel F, Soyka M, Botwin GJ, Morgan TR, Seth D. Brief report: genetics of alcoholic cirrhosis-GenomALC multinational study. Alcohol Clin Exp Res 2016; 39:836-42. [PMID: 25872595 PMCID: PMC4398999 DOI: 10.1111/acer.12693] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 01/29/2015] [Indexed: 12/20/2022]
Abstract
Background The risk of alcohol‐related liver cirrhosis increases with increasing alcohol consumption, but many people with very high intake escape from liver disease. We postulate that susceptibility to alcoholic cirrhosis has a complex genetic component and propose that this can be dissected through a large and sufficiently powered genomewide association study (GWAS). Methods The GenomALC Consortium comprises researchers from Australia, France, Germany, Switzerland, United Kingdom, and United States, with a joint aim of exploring the genetic and genomic basis of alcoholic cirrhosis. For this National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism funded study, we are recruiting high‐risk drinkers who are either cases (with alcoholic cirrhosis) or controls (drinking comparable amounts over similar time, but free of significant liver disease). Extensive phenotypic data are obtained using semistructured interviews and patient records, and blood samples are collected. Results We have successfully recruited 859 participants including 538 matched case–control samples as of September 2014, using study‐specific inclusion–exclusion criteria and data collection protocols. Of these, 580 are cases (442 men and 138 women) and 279 are controls (205 men and 74 women). Duration of excessive drinking was slightly greater in cases than controls and was significantly less in women than men. Cases had significantly lower lifetime alcohol intake than controls. Both cases and controls had a high prevalence of reported parental alcohol problems, but cases were significantly more likely to report that a father with alcohol problems had died from liver disease (odds ratio 2.53, 95% confidence interval 1.31 to 4.87, p = 0.0055). Conclusions Recruitment of participants for a GWAS of alcoholic cirrhosis has proved feasible across countries with multiple sites. Affected patients often consume less alcohol than unaffected ones, emphasizing the existence of individual vulnerability factors. Cases are more likely to report liver disease in a father with alcohol problems than controls, consistent with a potential genetic component to the risk of alcoholic cirrhosis.
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Affiliation(s)
- John B Whitfield
- Department of Genetic Epidemiology , QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
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Khemiri L, Kuja-Halkola R, Larsson H, Jayaram-Lindström N. Genetic overlap between impulsivity and alcohol dependence: a large-scale national twin study. Psychol Med 2016; 46:1091-1102. [PMID: 26671289 DOI: 10.1017/s0033291715002652] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
BACKGROUND Alcohol dependence is associated with increased levels of impulsivity, but the genetic and environmental underpinnings of this overlap remain unclear. The purpose of the current study was to investigate the degree to which genetic and environmental factors contribute to the overlap between alcohol dependence and impulsivity. METHOD Univariate and bivariate twin model fitting was conducted for alcohol dependence and impulsivity in a national sample of 16 819 twins born in Sweden from 1959 to 1985. RESULTS The heritability estimate for alcohol dependence was 44% [95% confidence interval (CI) 31-57%] for males and 62% (95% CI 52-72%) for females. For impulsivity, the heritability was 33% (95% CI 30-36%) in males and females. The bivariate twin analysis indicated a statistically significant genetic correlation between alcohol dependence and impulsivity of 0.40 (95% CI 0.23-0.58) in males and 0.20 (95% CI 0.07-0.33) in females. The phenotypic correlation between alcohol dependence and impulsivity was 0.20 and 0.17 for males and females, respectively, and the bivariate heritability was 80% (95% CI 47-117%) for males and 53% (95% CI 19-86%) for females. The remaining variance in all models was accounted for by non-shared environmental factors. CONCLUSIONS The association between alcohol dependence and impulsivity can be partially accounted for by shared genetic factors. The genetic correlation was greater in men compared with women, which may indicate different pathways to the development of alcohol dependence between sexes. The observed genetic overlap has clinical implications regarding treatment and prevention, and partially explains the substantial co-morbidity between alcohol dependence and psychiatric disorders characterized by impulsive behaviour.
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Affiliation(s)
- L Khemiri
- Department of Clinical Neuroscience,Centre for Psychiatric Research,Karolinska Institutet,Stockholm,Sweden
| | - R Kuja-Halkola
- Department of Medical Epidemiology and Biostatistics,Karolinska Institutet,Stockholm,Sweden
| | - H Larsson
- Department of Medical Epidemiology and Biostatistics,Karolinska Institutet,Stockholm,Sweden
| | - N Jayaram-Lindström
- Department of Clinical Neuroscience,Centre for Psychiatric Research,Karolinska Institutet,Stockholm,Sweden
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