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Germani G, D’Arcangelo F, Grasso M, Burra P. Advances and Controversies in Acute Alcohol-Related Hepatitis: From Medical Therapy to Liver Transplantation. Life (Basel) 2023; 13:1802. [PMID: 37763206 PMCID: PMC10532507 DOI: 10.3390/life13091802] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 09/29/2023] Open
Abstract
Alcohol-related hepatitis (AH) is a clinical syndrome characterized by recent-onset jaundice in the context of alcohol consumption. In patients with severe AH "unresponsive" to steroid therapy, mortality rates exceed 70% within six months. According to European and American guidelines, liver transplantation (LT) may be considered in highly selected patients who do not respond to medical therapy. The aim of this narrative review is to summarize current knowledge from medical therapy to liver transplantation in acute alcohol-related hepatitis. Due to the impossibility to guarantee six-month abstinence, LT for AH is controversial. Principal concerns are related to organ scarcity in the subset of stigma of "alcohol use disorder" (AUD) and the risk of relapse to alcohol use after LT. Return to alcohol use after LT is a complex issue that cannot be assessed as a yes/no variable with heterogeneous results among studies. In conclusion, present data indicate that well-selected patients have excellent outcomes, with survival rates of up to 100% at 24 and 36 months after LT. Behavioral therapy, ongoing psychological support, and strong family support seem essential to improve long-term outcomes after LT and reduce the risk in relapse of alcohol use.
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Affiliation(s)
- Giacomo Germani
- Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy
| | - Francesca D’Arcangelo
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Marco Grasso
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
| | - Patrizia Burra
- Gastroenterology and Multivisceral Transplant Unit, Azienda Ospedale—Università Padova, Department of Surgery, Oncology and Gastroenterology, University of Padova, 35122 Padova, Italy; (F.D.); (M.G.); (P.B.)
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Roy N, Nadda N, Kumar H, Prasad C, Kumar Jha J, Pandey HC, Vanamail P, Saraya A, Balhara YPS, Shalimar, Nayak B. Pattern recognition receptor CD14 gene polymorphisms in alcohol use disorder patients and its Influence on liver disease susceptibility. Front Immunol 2022; 13:975027. [PMID: 36238273 PMCID: PMC9551314 DOI: 10.3389/fimmu.2022.975027] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
Background Alcohol use disorders (AUDs) leading to liver disease is major concern over other spectrum of disorder. Excessive alcohol consumption resulting in leaky gut syndrome is attributed to alcohol-induced liver injury through portal translocation of bacterial endotoxin. Susceptibility to alcoholic liver disease (ALD) in AUD patients could be dependent upon genes responsible for inflammation and alcohol metabolism. The pattern recognition receptor CD14 gene is a major player in endotoxin-mediated inflammation and susceptibility to ALD. This study investigated the genetic association of CD14 polymorphisms and other mechanisms relevant to altered inflammatory responses leading to ALD. Methods Patients with alcohol use disorder with ALD (n = 128) and without liver disease (ALC, n = 184) and controls without alcohol use disorder (NALC, n = 152) from North India were enrolled. The CD4 gene polymorphisms in the North Indian population were evaluated by RFLP and sequencing. Secretory CD14 (sCD14), LBP, TLR4, MD2, TNFα, IL1b, IFNγ, IL6, IL10, and IL4 levels in serum were measured by ELISA among groups. The influence of polymorphisms on CD14 gene promoter activity and circulatory bacterial DNA level was determined. Results The CD14 gene promoter and exonic region SNPs were found to be monomorphic, except for SNP rs2569190 for the North Indian population. The genetic association of SNP rs2569190(C/T) with the risk of developing ALD was found significant for TT genotype [ORTT, 95% CI = 2.19, 1.16–4.13 for ALD vs. ALC and OR, 2.09, 1.18–3.72 for ALD vs. NALC]. An increased sCD14 level was observed in AUD patients compared to NALC control. Increased levels of LBP, TLR4, TNFα, IL1β, IFNγ, and IL6 and reduced levels of MD2, IL10, and IL4 were observed among the ALD patients compared to the other two control groups. Elevated levels of pro-inflammatory and reduced levels of anti-inflammatory cytokines were observed in the risk genotype TT groups of ALD patients and the ALC group compared to NALC. Promoter activity was observed in the intronic region flanking SNPs and risk genotype can influence reporter activity, indicating CD14 gene expression. Conclusion Enhanced CD14 expression associated with inflammatory responses increases susceptibility to ALD in the TT genotype of AUD patients.
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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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Alharshawi K, Fey H, Vogle A, Klenk T, Kim M, Aloman C. Alcohol Consumption Accumulation of Monocyte Derived Macrophages in Female Mice Liver Is Interferon Alpha Receptor Dependent. Front Immunol 2021; 12:663548. [PMID: 33995391 PMCID: PMC8119877 DOI: 10.3389/fimmu.2021.663548] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 04/20/2021] [Indexed: 12/12/2022] Open
Abstract
Monocytes develop in the bone marrow from the hematopoietic stem cells and represent heterogeneous phagocyte cells in the circulation. In homeostatic and inflammatory conditions, after recruitment into tissues, monocytes differentiate into macrophages and dendritic cells. Alcohol use causes about 3.3 million worldwide deaths per year, which is about 5.9% of all deaths. In the United States and Europe, alcohol use disorders represent the fifth leading cause of death. Females are more susceptible to alcoholic liver injury in both humans and mice. Strikingly, we still do not know how much of this difference in tissue injury is due to the differential effect of alcohol and its toxic metabolites on a) parenchymal or resident cells and/or b) immune response to alcohol. Therefore, we used a model of chronic alcohol exposure in mice to investigate the dynamics of monocytes, an innate immune cell type showed to be critical in alcoholic liver injury, by using immunophenotypic characterization. Our data reveal a sex-dimorphism of alcohol response of hepatic monocytes in female mice that is interferon receptor alpha dependent. This dimorphism could shed light on potential cellular mechanism(s) to explain the susceptibility of females to alcoholic immunopathogenesis and suggests an additional targetable pathway for alcoholic liver injury in females.
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Affiliation(s)
- Khaled Alharshawi
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, United States
| | - Holger Fey
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, United States
| | - Alyx Vogle
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, United States
| | - Tori Klenk
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, United States
| | - Miran Kim
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, United States
| | - Costica Aloman
- Division of Digestive Diseases and Nutrition, Section of Hepatology, Rush University, Chicago, IL, United States
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Choudhary NS, Duseja A. Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol 2021; 6:2. [PMID: 33409397 DOI: 10.21037/tgh.2019.09.06] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 09/04/2019] [Indexed: 12/12/2022] Open
Abstract
Inter-individual and inter-ethnic differences and difference in the severity and progression of liver disease among patients with non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) suggests the involvement of genetic and epigenetic factors in their pathogenesis. This article reviews the genetic and epigenetic modifiers in patients with NAFLD and ALD. Evidence regarding the genetic and epigenetic disease modifiers of NAFLD and ALD was reviewed by searching the available literature. Both genome wide association studies (GWAS) and candidate gene studies pertaining to the pathogenesis in both diseases were included. Clinical implications of the available information are also discussed. Several studies have shown association of both NAFLD and ALD with I148M PNPLA3 variant. In addition to the higher prevalence of hepatic steatosis, the I148M PNPLA3 variant is also associated with severity of liver disease and risk of hepatocellular carcinoma (HCC). TM6SF2 is the other genetic variant shown to be significantly associated with hepatic steatosis and cirrhosis in patients with NAFLD and ALD. The Membrane bound O-acyltransferase domain-containing 7 (MBOAT7) genetic variant is also associated with both NAFLD and ALD. In addition to these mutations, several variants related to the genes involved in glucose metabolism, insulin resistance, lipid metabolism, oxidative stress, inflammatory pathways, fibrosis have also been shown to be the disease modifiers in patients with NAFLD and ALD. Epigenetics involving several micro RNAs and DNA methylation could also modify the disease course in NAFLD and ALD. In conclusion the available literature suggests that genetics and epigenetics are involved in the pathogenesis of NAFLD and ALD which may affect the disease prevalence, severity and response to treatment in these patients.
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Affiliation(s)
- Narendra Singh Choudhary
- Institute of Liver Transplantation and Regenerative Medicine, Medanta, The Medicity, Gurgaon, Delhi (NCR), India
| | - Ajay Duseja
- Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Alvarez Cooper I, Beecher K, Chehrehasa F, Belmer A, Bartlett SE. Tumour Necrosis Factor in Neuroplasticity, Neurogenesis and Alcohol Use Disorder. Brain Plast 2020; 6:47-66. [PMID: 33680846 PMCID: PMC7903009 DOI: 10.3233/bpl-190095] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Alcohol use disorder is a pervasive and detrimental condition that involves changes in neuroplasticity and neurogenesis. Alcohol activates the neuroimmune system and alters the inflammatory status of the brain. Tumour necrosis factor (TNF) is a well characterised neuroimmune signal but its involvement in alcohol use disorder is unknown. In this review, we discuss the variable findings of TNF's effect on neuroplasticity and neurogenesis. Acute ethanol exposure reduces TNF release while chronic alcohol intake generally increases TNF levels. Evidence suggests TNF potentiates excitatory transmission, promotes anxiety during alcohol withdrawal and is involved in drug use in rodents. An association between craving for alcohol and TNF is apparent during withdrawal in humans. While anti-inflammatory therapies show efficacy in reversing neurogenic deficit after alcohol exposure, there is no evidence for TNF's essential involvement in alcohol's effect on neurogenesis. Overall, defining TNF's role in alcohol use disorder is complicated by poor understanding of its variable effects on synaptic transmission and neurogenesis. While TNF may be of relevance during withdrawal, the neuroimmune system likely acts through a larger group of inflammatory cytokines to alter neuroplasticity and neurogenesis. Understanding the individual relevance of TNF in alcohol use disorder awaits a more comprehensive understanding of TNF's effects within the brain.
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Affiliation(s)
- Ignatius Alvarez Cooper
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
| | - Kate Beecher
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
- School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Fatemeh Chehrehasa
- School of Biomedical Sciences, Queensland University of Technology, Brisbane, Australia
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
| | - Arnauld Belmer
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
- School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
| | - Selena E. Bartlett
- Institute of Health and Biomedical Innovation, Translational Research Institute, Brisbane, Australia
- School of Clinical Sciences, Queensland University of Technology, Brisbane, Australia
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Sarcopenia is associated with longer hospital stay and multiorgan dysfunction in alcoholic hepatitis. Eur J Gastroenterol Hepatol 2020; 32:733-738. [PMID: 31834050 PMCID: PMC7196001 DOI: 10.1097/meg.0000000000001583] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Excessive alcohol consumption has steadily risen to become the third leading cause of preventable death in the USA. One consequence of heavy alcohol use recently under considerable investigation is alcoholic hepatitis. Although many risk factors for developing alcoholic hepatitis have been documented, our aim in this study was to examine the potential association between sarcopenia and severity, mortality, 30 days readmission rate, complication, infections and length of hospital stay in alcoholic hepatitis patients. METHODS A retrospective analysis was performed at a large, academic hospital in 194 alcoholic hepatitis patients aged 18-60 who had cross-sectional computed tomography imaging and met our clinical definition of alcoholic hepatitis. The fifth percentile of the psoas muscle index was used as a cutoff for sarcopenia. RESULTS One hundred ninety-four patients met the criteria for alcoholic hepatitis and had cross-sectional imaging. Higher Model for End-Stage Liver disease score was found in the sarcopenia group when compared to the non-sarcopenia group (mean Model for End-Stage Liver disease 21.5 and 24.2, respectively, P = 0.03). Sarcopenia also correlated with significantly longer hospital stay; the average length of stay in the sarcopenia group was 17.2 days while the non-sarcopenia patients had an average of 12.4 days. We found higher risk of developing pneumonia, sepsis and hepatic encephalopathy in sarcopenic patients. CONCLUSION Alcoholic hepatitis patients with sarcopenia have significantly worse outcomes when compared with the patients without sarcopenia, including a severe form of alcoholic hepatitis, longer hospital stays, higher risk of developing pneumonia, sepsis and hepatic encephalopathy.
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Du L, Gong T, Yao M, Dai H, Ren HG, Wang H. Contribution of the polymorphism rs1800469 of transforming growth factor β in the development of myocardial infarction: meta-analysis of 5460 cases and 8413 controls (MOOSE-compliant article). Medicine (Baltimore) 2019; 98:e15946. [PMID: 31261499 PMCID: PMC6617069 DOI: 10.1097/md.0000000000015946] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Studies investigating the association between transforming growth factor (TGF-β-509C/T, rs1800469) promoter polymorphism and myocardial infarction (MI) risk reported inconsistent results. The aim of our study was to assess the association between the 509C/T polymorphism of the TGF-β gene (rs1800469) and MI risk.A total of 5460 cases and 8413 controls in 7 case-control studies were incorporated in our current meta-analysis. The original studies were selected through searching the databases of the PubMed and EMBASE. The odds ratio (OR) and 95% confidence interval (95% CI) of TGF-β 509C/T (rs1800469) for MI risk were applied to estimate the strength of the association.Our results showed that T allele carriers had a 13% increased risk of MI, when compared with the C allele carriers (OR = 1.13, 95% CI: 1.00-1.27). In the subset analysis by the type of MI, significantly elevated risk of MI was associated with the homozygote TT and heterozygote C/T in no-AMI subjects, when compared with the CC homozygote carriers (OR = 1.12, 95% CI:1.02-1.23).Our meta-analysis shows that the polymorphism with homozygote TT and heterozygote C/T of TGF-β 509C/T (rs1800469) is significantly associated with the increased risk of MI.
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Affiliation(s)
- Ling Du
- Department of Cardiovascular Medicine, Chong Gang Iron and Steel General Hospital, Great Dukou District, Chongqing City, China
| | - Tao Gong
- Department of Cardiovascular Medicine, Chong Gang Iron and Steel General Hospital, Great Dukou District, Chongqing City, China
| | - Minghui Yao
- Department of Cardiovascular Medicine, Chong Gang Iron and Steel General Hospital, Great Dukou District, Chongqing City, China
| | - Henghua Dai
- Department of Cardiovascular Medicine, Chong Gang Iron and Steel General Hospital, Great Dukou District, Chongqing City, China
| | - Hong Gang Ren
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN
| | - Haitao Wang
- Cardiac Surgery Center and Heart Failure Center of Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Affiliated Hospital of University of Electronic Science and Technology, China
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Abstract
Apart from the classic knowledge that ethanol mediates its hepatotoxicity through its metabolism to acetaldehyde, a well-known hepatotoxic molecule, recent research has elucidated several key mechanisms that potentiate ethanol's damage to the liver parenchyma, such as generation of free radicals, activation of Kupffer cells, and alterations to the human bacterial and fungal microbiome. Genetic studies have suggested the role of PNPLA3 and TM6SF2 gene mutations in the progression of alcoholic liver disease.
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Affiliation(s)
- Themistoklis Kourkoumpetis
- Department of Gastroenterology, Baylor College of Medicine, 6620 Main Street, Suite 1450, Houston, TX 77030, USA
| | - Gagan Sood
- Department of Surgery, Division of Abdominal Transplantation, Baylor College of Medicine, 6620 Main Street, Suite 1450, Houston, TX 77030, USA.
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10
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Zahr NM. Peripheral TNFα elevations in abstinent alcoholics are associated with hepatitis C infection. PLoS One 2018; 13:e0191586. [PMID: 29408932 PMCID: PMC5800541 DOI: 10.1371/journal.pone.0191586] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 01/08/2018] [Indexed: 12/31/2022] Open
Abstract
Substantial evidence supports the view that inflammatory processes contribute to brain alterations in HIV infection. Mechanisms recently proposed to underlie neuropathology in Alcohol Use Disorder (AUD) include elevations in peripheral cytokines that sensitize the brain to the damaging effects of alcohol. This study included 4 groups: healthy controls, individuals with AUD (abstinent from alcohol at examination), those infected with HIV, and those comorbid for HIV and AUD. The aim was to determine whether inflammatory cytokines are elevated in AUD as they are in HIV infection. Cytokines showing group differences included interferon gamma-induced protein 10 (IP-10) and tumor necrosis factor α (TNFα). Follow-up t-tests revealed that TNFα and IP-10 were higher in AUD than controls but only in AUD patients who were seropositive for Hepatitis C virus (HCV). Specificity of TNFα and IP-10 elevations to HCV infection status was provided by correlations between cytokine levels and HCV viral load and indices of liver integrity including albumin/globulin ratio, fibrosis scores, and AST/platelet count ratio. Because TNFα levels were mediated by HCV infection, this study provides no evidence for elevations in peripheral cytokines in "uncomplicated", abstinent alcoholics, independent of liver disease or HCV infection. Nonetheless, these results corroborate evidence for elevations in IP-10 and TNFα in HIV and for IP-10 levels in HIV+HCV co-infection.
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Affiliation(s)
- Natalie M. Zahr
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, United States of America
- Neuroscience Department, SRI International, Menlo Park, CA, United States of America
- * E-mail:
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11
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Nahon P, Nault JC. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma. Liver Int 2017; 37:1591-1601. [PMID: 28296015 DOI: 10.1111/liv.13419] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/08/2017] [Indexed: 02/13/2023]
Abstract
Exploration of the constitutional genetics of hepatocellular carcinoma (HCC) has identified numerous variants associated with a higher risk of liver cancer in alcoholic cirrhotic patients. Although Genome-Wide Association studies have not been carried out in the field of alcohol-related HCC, common single nucleotide polymorphisms conferring a small increase in the risk of liver cancer risk have been identified and shown to modulate ethanol metabolism, inflammation, oxidative stress, iron or lipid metabolism. Specific patterns of gene mutations including CTNNB1, TERT, ARID1A and SMARCA2 exist in alcohol-related HCC. Moreover, a specific mutational process observed at the nucleotide level by next generation sequencing has revealed cooperation between alcohol and tobacco in the development of HCC. Combining this genetic information with epidemiological and clinical data that might define specific HCC risk classes and refine surveillance strategies needs to be assessed in large prospective cohorts of patients with alcoholic cirrhosis.
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Affiliation(s)
- Pierre Nahon
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
| | - Jean-Charles Nault
- AP-HP, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, France.,Université Paris 13, Bobigny, France.,Inserm UMR-1162, "Functional Genetics of Solid Tumours", Université Paris Descartes, Université Paris Diderot, Université Paris 13, Labex Oncoimmunology, Equipe labellisée Ligue contre le Cancer, Paris, France
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12
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Iida-Ueno A, Enomoto M, Tamori A, Kawada N. Hepatitis B virus infection and alcohol consumption. World J Gastroenterol 2017; 23:2651-2659. [PMID: 28487602 PMCID: PMC5403744 DOI: 10.3748/wjg.v23.i15.2651] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Revised: 01/25/2017] [Accepted: 03/02/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer, and the second most common cause of cancer deaths worldwide. The top three causes of HCC are hepatitis B virus (HBV), hepatitis C virus (HCV), and alcoholic liver disease. Owing to recent advances in direct-acting antiviral agents, HCV can now be eradicated in almost all patients. HBV infection and alcoholic liver disease are expected, therefore, to become the leading causes of HCC in the future. However, the association between alcohol consumption and chronic hepatitis B in the progression of liver disease is less well understood than with chronic hepatitis C. The mechanisms underlying the complex interaction between HBV and alcohol are not fully understood, and enhanced viral replication, increased oxidative stress and a weakened immune response could each play an important role in the development of HCC. It remains controversial whether HBV and alcohol synergistically increase the incidence of HCC. Herein, we review the currently available literature regarding the interaction of HBV infection and alcohol consumption on disease progression.
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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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Novo-Veleiro I, Cieza-Borrella C, Pastor I, Chamorro AJ, Laso FJ, González-Sarmiento R, Marcos M. A Single Nucleotide Polymorphism in the RASGRF2 Gene Is Associated with Alcoholic Liver Cirrhosis in Men. PLoS One 2016; 11:e0168685. [PMID: 27992614 PMCID: PMC5167392 DOI: 10.1371/journal.pone.0168685] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/05/2016] [Indexed: 11/18/2022] Open
Abstract
Background Genetic polymorphisms in the RAS gene family are associated with different diseases, which may include alcohol-related disorders. Previous studies showed an association of the allelic variant rs26907 in RASGRF2 gene with higher alcohol intake. Additionally, the rs61764370 polymorphism in the KRAS gene is located in a binding site for the let-7 micro-RNA family, which is potentially involved in alcohol-induced inflammation. Therefore, this study was designed to explore the association between these two polymorphisms and susceptibility to alcoholism or alcoholic liver disease (ALD). Methods We enrolled 301 male alcoholic patients and 156 healthy male volunteers in this study. Polymorphisms were genotyped by using TaqMan® PCR assays for allelic discrimination. Allelic and genotypic frequencies were compared between the two groups. Logistic regression analysis was performed to analyze the inheritance model. Results The A allele of the RASGRF2 polymorphism (rs26907) was significantly more prevalent among alcoholic patients with cirrhosis (23.2%) compared to alcoholic patients without ALD (14.2%). This difference remained significant in the group of patients with alcohol dependence (28.8% vs. 14.3%) but not in those with alcohol abuse (15.1% vs. 14.4%). Multivariable logistic regression analysis showed that the A allele of this polymorphism (AA or GA genotype) was associated with alcoholic cirrhosis both in the total group of alcoholics (odds ratio [OR]: 2.33, 95% confidence interval [CI]: 1.32–4.11; P = 0.002) and in the group of patients with alcohol dependence (OR: 3.1, 95% CI: 1.50–6.20; P = 0.001). Allelic distributions of the KRAS polymorphism (rs61764370) did not differ between the groups. Conclusions To our knowledge, this genetic association study represents the first to show an association of the RASGRF2 G>A (rs26907) polymorphism with ALD in men, particularly in the subgroup of patients with AD. The findings suggest the potential relevance of the RAS gene family in alcoholism and ALD.
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Affiliation(s)
- Ignacio Novo-Veleiro
- Department of Internal Medicine, University Hospital of Santiago de Compostela, A Coruña, Spain
| | - Clara Cieza-Borrella
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
| | - Isabel Pastor
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
| | - Antonio-Javier Chamorro
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
| | - Francisco-Javier Laso
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
| | - Rogelio González-Sarmiento
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
| | - Miguel Marcos
- Molecular Medicine Unit, Department of Medicine, University of Salamanca, Salamanca, Spain
- Institute of Biomedical Research of Salamanca-IBSAL, Salamanca, Spain
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Salamanca, Spain
- * E-mail:
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15
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Yeluru A, Cuthbert JA, Casey L, Mitchell MC. Alcoholic Hepatitis: Risk Factors, Pathogenesis, and Approach to Treatment. Alcohol Clin Exp Res 2016; 40:246-55. [PMID: 26842243 DOI: 10.1111/acer.12956] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Accepted: 11/02/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND Alcoholic hepatitis (AH) is an inflammatory disorder of the liver characterized clinically by jaundice, hepatomegaly, and abdominal pain, and histologically by macrovesicular steatosis and necroinflammation. METHODS This clinical review will cover what is known about the pathogenesis, clinical presentation, current treatments, and novel therapies for AH. RESULTS The pathogenesis and treatment of AH remain areas of active research. Although abstinence is the cornerstone of therapy for all stages of alcoholic liver disease, corticosteroids have shown modest short-term benefits in treatment of severe AH. CONCLUSIONS Improved understanding of the pathogenesis of AH has expanded the range of potential treatments for this devastating disease. Several novel therapies are also currently in various stages of testing through clinical trials.
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Affiliation(s)
| | - Jennifer A Cuthbert
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Lisa Casey
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
| | - Mack C Mitchell
- Division of Digestive and Liver Diseases, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas
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16
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Zhao YY, Xiao M, Zhang CL, Xie KQ, Zeng T. Associations between the tumor necrosis factor-α gene and interleukin-10 gene polymorphisms and risk of alcoholic liver disease: A meta-analysis. Clin Res Hepatol Gastroenterol 2016; 40:428-39. [PMID: 26656007 DOI: 10.1016/j.clinre.2015.10.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/15/2015] [Accepted: 10/28/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND The critical roles of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in the pathogenesis of alcoholic liver diseases (ALD) suggest that functional variations in the TNF-α (TNFA) and IL-10 genes may be related to individual susceptibility to ALD. As available studies examining the associations between TNFA or IL-10 polymorphisms and ALD risk have yielded conflicting results, a meta-analysis was conducted to clarify the potential relation between TNFA and IL-10 polymorphisms and the risk of ALD. METHODS A comprehensive literature search was conducted to identify relevant studies. Pooled odds ratios and 95% confidence intervals were calculated using a random-effects model. The heterogeneity between studies was assessed using the Cochran's Q statistic and the I(2) statistic. Publication bias was assessed using funnel plots and the Egger's regression test. RESULTS A total of 17studies and 12studies were identified and included in the meta-analysis of the associations between TNFA polymorphisms and ALD risk, and IL-10 polymorphisms and ALD risk, respectively. The pooled results showed that the "A" allele of the TNFA-238G>A polymorphism was significantly associated with an increased risk of ALD. Significant differences in the allele and genotype distributions of the IL-10-1082A>G polymorphism were detected in the comparison between ALD patients and healthy controls, but not when comparing ALD patients and alcohol dependent individuals without ALD. No significant associations between other polymorphic loci and ALD risks were detected. CONCLUSIONS The TNFA-238G>A polymorphism was significantly associated with ALD risk, while the TNFA-308G>A polymorphism and IL-10 polymorphisms (-1082A>G and -592C>A) may not be associated with the individual susceptibility to ALD. The impact of combined TNFA and IL-10 polymorphisms on individual susceptibility to ALD needs to be investigated in future studies.
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Affiliation(s)
- Yu-Ying Zhao
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Mo Xiao
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Cui-Li Zhang
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Ke-Qin Xie
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China
| | - Tao Zeng
- Institute of Toxicology, School of Public Health, Shandong University, 44, Wenhua West Road, Jinan City, Shandong Province, 250012, PR China.
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17
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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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Abstract
Alcoholic liver disease (ALD) is a leading cause of liver-related morbidity and mortality worldwide. ALD encompasses a spectrum of disorders including asymptomatic steatosis, steatohepatitis, fibrosis, cirrhosis and its related complications, and the acute-on-chronic state of alcoholic hepatitis. While multidisciplinary efforts continue to be aimed at curbing progression of this spectrum of disorders, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of ALD. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with severe AH is very high (20-50 % at 3 months). The current therapeutic regimens are limited. The development of new therapies requires translational studies in human samples and suitable animal models that reproduce clinical and histological features of human AH. This review article summarizes the clinical syndrome, pre-clinical translational tools, and pathogenesis of AH at a molecular and cellular level, with the aim of identifying new targets of potential therapeutic intervention.
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19
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Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016. [PMID: 26819510 DOI: 10.3748/wjg.v22.i4.141] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
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Affiliation(s)
- Ignacio Novo-Veleiro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Lucía Alvela-Suárez
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Antonio-Javier Chamorro
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Rogelio González-Sarmiento
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Francisco-Javier Laso
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
| | - Miguel Marcos
- Ignacio Novo-Veleiro, Lucía Alvela-Suárez, Department of Internal Medicine, University Hospital of Santiago de Compostela, 37007 Salamanca, Spain
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20
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Novo-Veleiro I, Alvela-Suárez L, Chamorro AJ, González-Sarmiento R, Laso FJ, Marcos M. Alcoholic liver disease and hepatitis C virus infection. World J Gastroenterol 2016; 22:1411-1420. [PMID: 26819510 PMCID: PMC4721976 DOI: 10.3748/wjg.v22.i4.1411] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 10/01/2015] [Accepted: 12/01/2015] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption and hepatitis C virus (HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher (up to 50%) in alcoholic patients than in the general population. However, the presence of advanced alcoholic liver disease (ALD) or intravenous drug use (IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefit from additional support during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.
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21
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Zhang L, Song FF, Huang YB, Zheng H, Song FJ, Chen KX. Association between the (GT)n polymorphism of the HO-1 gene promoter region and cancer risk: a meta-analysis. Asian Pac J Cancer Prev 2015; 15:4617-22. [PMID: 24969894 DOI: 10.7314/apjcp.2014.15.11.4617] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Several studies have previously focused on associations between the (GT)n repeat polymorphism of the heme oxygenase-1 (HO-1) gene promoter region and risk of cancers, but results are complex. We conducted the present meta-analysis to integrate relevant findings and evaluate the association between HO-1 (GT)n repeat polymorphism and cancer susceptibility. MATERIALS AND METHODS Published literature was retrieved from the PubMed/MEDLINE, EMBASE and ISI Web of Science databases before November 2013. For all alleles and genotypes, odds ratios were pooled to assess the strength of the associations using either fixed-effects or random-effects models according to heterogeneity. Subgroup analysis was conducted according to ethnicity and histopathology. RESULTS A total of 10 studies involving 2,367 cases and 2,870 controls were identified. The results showed there was no association between HO-1 (GT)n repeat polymorphism and the cancer risk both at the allelic and genotypic level. However, in the stratified analysis, we observed an increased risk of squamous cell carcinoma in persons carrying the LL genotype and the LL+LS genotype as compared with those carrying the SS genotype. When the LS and SS genotypes were combined, the odds ratio for squamous cell carcinoma in LL-genotype carriers, were also significantly increased. No publication bias was observed. CONCLUSIONS The LL genotype and L-allele carrying genotypes (LL+LS) of HO-1 (GT)n repeat polymorphism are potential genetic factors for developing squamous cell carcinoma. More large and well-designed studies are required for further validations.
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Affiliation(s)
- Ling Zhang
- Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer; Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China E-mail :
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22
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Nahon P, Sutton A, Ziol M, Zucman-Rossi J, Trinchet JC, Ganne-Carrié N. Genetic risk markers for hepatocellular carcinoma in patients with alcoholic liver disease. Hepat Oncol 2015; 2:63-78. [PMID: 30190987 DOI: 10.2217/hep.14.26] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Various single nucleotide polymorphisms have been reported to be associated with a higher risk of hepatocellular carcinoma in alcoholic cirrhotic patients. Until now, only common variants conferring a small increase in liver cancer risk have been identified. These inherited factors are able to modulate several biological pathways involved in alcohol-induced hepatocarcinogenesis, such as ethanol metabolism, inflammation, oxidative stress, or iron and lipid homeostasis. How the combination of these variants might collectively define an individual genomic risk prediction is currently being investigated. The other challenge in clinical practice lies in defining how to integrate this genetic information with other clinical parameters so as to refine selection of alcoholic cirrhotic patients according to various classes of hepatocellular carcinoma risk.
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Affiliation(s)
- Pierre Nahon
- Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France.,Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France
| | - Angela Sutton
- Service de Biochimie, Hôpital Jean Verdier, AP-HP, Bondy, France.,INSERM U1148, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,Service de Biochimie, Hôpital Jean Verdier, AP-HP, Bondy, France.,INSERM U1148, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France
| | - Marianne Ziol
- Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,Service d'Anatomo-Pathologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Centre de Ressources biologiques GH PSSD, Bondy, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,Service d'Anatomo-Pathologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Centre de Ressources biologiques GH PSSD, Bondy, France
| | - Jessica Zucman-Rossi
- Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France.,Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Université Paris Diderot, F-75013, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hopital Europeen Georges Pompidou, F-75015 Paris, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France.,Université Paris Descartes, Labex Immuno-Oncology, Sorbonne Paris Cité, Faculté de Médecine, Paris, France.,Université Paris Diderot, F-75013, Paris, France.,Assistance Publique-Hôpitaux de Paris, Hopital Europeen Georges Pompidou, F-75015 Paris, France
| | - Jean-Claude Trinchet
- Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France.,Centre de Ressources biologiques GH PSSD, Bondy, France.,Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France.,Centre de Ressources biologiques GH PSSD, Bondy, France
| | - Nathalie Ganne-Carrié
- Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France.,Service d'Hépatologie, Hôpital Jean Verdier, AP-HP, Bondy, France.,Université Paris 13, Sorbonne Paris Cité, UFR SMBH, F-93000 Bobigny, France.,INSERM, UMR-1162, Génomique fonctionnelle des Tumeurs solides, équipe labellisée "Ligue Contre Le Cancer", Paris, F-75010 France
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23
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Cheng K, Zhao YJ, Liu L, Wan JJ. Tumor necrosis factor-α 238 G/A polymorphism and risk of hepatocellular carcinoma: evidence from a meta-analysis. Asian Pac J Cancer Prev 2014; 14:3275-9. [PMID: 23803115 DOI: 10.7314/apjcp.2013.14.5.3275] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Tumor necrosis factor-α (TNF-α) plays a very important role in the development and progression of cancer. Many epidemiological studies have evaluated associations between the TNF-α 238 G/A polymorphism and hepatocellular carcinoma (HCC) risk, but the published data are inconclusive. Therefore, we performed the present meta-analysis. METHODS Electronic searches of several databases were conducted for all publications on the association between TNF-α 238 G/A polymorphism and HCC through July 2012. Asummary odds ratio (OR) with its 95% confidence interval (CI) were calculated to evaluate the strength of this association. RESULTS Eleven case-control studies with a total of 1,572 HCC cases and 1,875 controls were finally included in this meta-analysis. Overall, the TNF-α 238 G/A polymorphism was significantly associated with increased risk of hepatocellular carcinoma in three genetic comparison models (For A versus G: OR 1.32, 95%CI 1.04-1.69, P = 0.02, I2 = 40%; for AG versus GG: OR 1.32, 95%CI 1.02-1.71, P = 0.03, I2 = 40%; for AA/AG versus GG: OR 1.33, 95%CI 1.03-1.72, P = 0.03, I2 = 41%) when all studies were pooled. Subgroup analysis by ethnicity further showed that there was a significant association between the TNF-α 238 G/A polymorphism and risk of HCC in Asians under three genetic comparison models (For A versus G: OR 1.30, 95%CI 1.00-1.68, P = 0.05, I2 = 45% for AA/AG versus GG: OR 1.31, 95%CI 1.00-1.71, P = 0.05, I2 = 46%). CONCLUSIONS This meta-analysis provided convincing evidence that the TNF-α 238 G/A polymorphism is associated with increased susceptibility to HCC. However, more well-designed studies with large sample size are needed to validate this association in Caucasians.
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Affiliation(s)
- Ke Cheng
- 35 Ward of Transplantation, The Third Xiangya hospital of Central South University, Changsha, China
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24
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Chamorro AJ, Torres JL, Mirón-Canelo JA, González-Sarmiento R, Laso FJ, Marcos M. Systematic review with meta-analysis: the I148M variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is significantly associated with alcoholic liver cirrhosis. Aliment Pharmacol Ther 2014; 40:571-81. [PMID: 25060292 DOI: 10.1111/apt.12890] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 05/02/2014] [Accepted: 07/07/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND Several studies have reported an association between alcoholic liver cirrhosis (ALC) or other forms of alcoholic liver disease (ALD) and the genetic variant rs738409 (C>G) in adiponutrin/patatin-like phospholipase domain-containing 3 gene (PNPLA3). AIM To evaluate the influence of this variant on ALC and other forms of ALD. METHODS We performed a systematic review of previous studies on the relationship between rs738409 of PNPLA3 and ALD and meta-analysis was conducted in a random-effects model. Calculations of the odds ratios (ORs) and their confidence intervals (CIs), tests for heterogeneity and sensitivity analyses were performed. RESULTS Database search identified 11 previous studies available for inclusion with a total of 3495 patients with ALD (2087 with ALC) and 5038 controls (4007 healthy subjects and 1031 alcoholics without ALD). Patients with ALC compared to controls had a significantly higher prevalence of the G allele when comparing GG vs. CC (OR 4.30, 95% CI 3.25-5.69; P < 0.00001) or GC vs. CC genotypes (GC vs. CC: OR 1.91, 95% CI 1.67-2.17) or under a recessive or dominant model. Similar results were found when comparing separately patients with ALC vs. alcoholics without ALD or healthy subjects. An association of the G allele with ALD emerged when comparing ALD patients vs. alcoholics without ALD and/or healthy subjects although moderate to large heterogeneity was observed. Our data suggested an additive genetic model for this variant in ALD. CONCLUSION Our meta-analysis shows that the rs738409 variant of PNPLA3 is clearly associated with alcoholic liver cirrhosis.
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Affiliation(s)
- A-J Chamorro
- Alcoholism Unit, Department of Internal Medicine, University Hospital of Salamanca, Institute of Biomedical Research of Salamanca (IBSAL), Salamanca, Spain
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25
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Toshikuni N, Tsutsumi M, Arisawa T. Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease. World J Gastroenterol 2014; 20:8393-8406. [PMID: 25024597 PMCID: PMC4093692 DOI: 10.3748/wjg.v20.i26.8393] [Citation(s) in RCA: 102] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Revised: 01/29/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) are serious health problems worldwide. These two diseases have similar pathological spectra, ranging from simple hepatic steatosis to steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis, a small percentage of individuals will develop progressive liver disease. Notably, both ALD and NAFLD are frequently accompanied by extrahepatic complications, including cardiovascular disease and malignancy. The survival of patients with ALD and NAFLD depends on various disease-associated conditions. This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology, the factors associated with disease susceptibility and progression, and the predictors and characteristics of outcomes. A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.
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Yang AM, Wen LL, Yang CS, Wang SC, Chen CS, Bair MJ. Interleukin 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients. Kaohsiung J Med Sci 2014; 30:291-8. [PMID: 24835349 DOI: 10.1016/j.kjms.2014.02.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Revised: 02/24/2014] [Accepted: 12/11/2013] [Indexed: 12/20/2022] Open
Abstract
Alcoholic liver cirrhosis is a severe form of alcohol-related liver damage. More than 95% of heavy drinkers develop a fatty liver, but only 35% of them develop cirrhosis. We postulate that genetic factors may play a role in this difference. Genetic polymorphisms of the cytokine genes may influence Kupffer cells cytokine genes expression. In this study, we evaluated the promoter polymorphisms of interleukin (IL) 1β, IL 6, IL 10, and tumor necrosis factor alpha (TNFα) and aimed to clarify the association between the polymorphisms and the disease. Forty alcoholic patients with liver cirrhosis and 64 healthy volunteers were included in our investigation. Genotyping on IL 1β -511 T>C, IL 6 -572 G>C, IL 10 -819 C>T, IL 10 -1082 G>A, and TNFα -308 G>A was done. Another 36 patients with recurrent alcoholic pancreatitis were included as an additional control group. Genotyping on IL 10 -819 C>T and IL 10 -1082 G>A was done. The polymorphisms on IL 1 and IL 6 showed no significant association. The p value for TNFα -308 G>A was 0.028 in comparison with healthy volunteers. Although the p value was less than 0.05, it did not reach significance after Bonferroni correction. The p values for IL 10 -819 C>T and IL 10 -1082 G>A were respectively 0.031 and 0.026 in healthy volunteers and 0.028 and 0.023 in the alcoholic pancreatitis group. The results also did not reach significance after Bonferroni correction. Among the participants with the GCC haplotype, healthy volunteers had p = 0.027 (p < 0.05) and an odds ratio (OR) of 0.124 [confidence interval (95%) CI, 0.015-0.997], whereas the alcoholic pancreatitis group had p = 0.023 (p < 0.05) and an OR of 0.106 (95% CI, 0.012-0.912). The odds ratio of people having one ATA haplotype was 6.233 (95% CI, 0.739-52.547) in healthy volunteers and 6.588 (95% CI, 0.727-59.679) in the alcoholic pancreatitis group; the corresponding rate was 10.521 (95% CI, 1.252-88.440) and 12.833 (95% CI 1.408-117.008) for people with two ATA haplotypes. The p values in these groups were 0.031 (p < 0.05) and 0.028 (p < 0.05), respectively. The presence of a GCC haplotype could have protective effect against alcoholic liver disease, whereas the presence of an ATA haplotype could predispose carriers to the disease. The IL 10 promoter haplotype is associated with alcoholic liver cirrhosis in Taiwanese patients.
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Affiliation(s)
- An-Ming Yang
- Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan; Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Li-Li Wen
- Department of Laboratory Medicine, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Chang-Shyue Yang
- Department of Internal Medicine, En Chu Kong Hospital, New Taipei City, Taiwan
| | - Sun-Chong Wang
- Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Chien-Sheng Chen
- Institute of Systems Biology and Bioinformatics, National Central University, Jhongli City, Taiwan
| | - Ming-Jong Bair
- Department of Internal Medicine, Mackay Memorial Hospital, Taitung Branch, Taitung, Taiwan.
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Association between CD14-159C>T polymorphisms and the risk for alcoholic liver disease: a meta-analysis. Eur J Gastroenterol Hepatol 2013; 25:1183-9. [PMID: 23587862 DOI: 10.1097/meg.0b013e3283612ff1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIMS The association between CD14-159C>T polymorphisms and alcoholic liver disease (ALD) risk has been investigated in many studies, but the results were inconsistent. Therefore, we performed a meta-analysis to investigate the association between the CD14-159C>T polymorphisms and the risk for ALD. METHODS A comprehensive literature search was conducted to identify the relevant studies from PubMed, ISI Web of Science, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using either the fixed-effects model or random-effects model on the basis of the heterogeneity test. RESULTS A total of eight eligible studies were included in the meta-analyses. The combined results showed no significant association between CD14-159C>T polymorphisms and ALD risk when ALD patients were compared with alcoholics without ALD (T vs. C, OR=1.22, 95% CI 0.84-1.77; TT/TC vs. CC, OR=1.43, 95% CI 0.86-2.37) and when ALD patients were compared with nonalcoholics (T vs. C, OR=1.13, 95% CI 0.90-1.43; TT/TC vs. CC, OR=1.05, 95% CI 0.76-1.46). However, a significant association was observed in the heterozygous comparison (TC vs. CC, OR=3.47, 95% CI 1.93-6.22), whereas a marginal association was observed in the dominant model (TT/CT vs. CC, OR=2.43, 95% CI 1.00-5.91) when alcoholic cirrhosis patients were compared with alcoholics without ALD. CONCLUSION This meta-analysis suggests that the CD14-159C>T polymorphism may not be significantly associated with the risk for ALD. Although a significant association was observed between the -159C>T polymorphism and the risk for alcoholic cirrhosis, well-designed studies with large sample sizes are warranted to confirm these results.
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Cerović I, Mladenović D, Ješić R, Naumović T, Branković M, Vučević D, Aleksić V, Radosavljević T. Alcoholic liver disease/nonalcoholic fatty liver disease index: distinguishing alcoholic from nonalcoholic fatty liver disease. Eur J Gastroenterol Hepatol 2013; 25:899-904. [PMID: 23426271 DOI: 10.1097/meg.0b013e32835f0786] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVE The alcoholic liver disease (ALD)/nonalcoholic fatty liver disease (NAFLD) (ANI) scoring system was constructed as a response to a clinical need for avoiding the risks of liver biopsy in diagnosing the etiology of fatty liver disease. The aim of this study was to test the reliability of ANI as a noninvasive method to distinguish ALD from NAFLD. MATERIALS AND METHODS One hundred and thirty-five patients were classified into two groups, ALD and NAFLD, according to the pathohistological results. Parameters for ANI are aspartate aminotransferase, alanine aminotransferase, mean corpuscular volume, BMI, and sex. ANI was calculated using an online calculator, official site of Mayo Clinic. RESULTS ANI was significantly higher in patients with ALD than NAFLD (P<0.01). The cutoff point of ANI is -0.66. ANI greater than -0.66 indicates ALD, whereas ANI less than -0.66 yields a higher probability of NAFLD with high specificity (96.7%) and sensitivity (84.1%). The mean corpuscular volume and aspartate aminotransferase/alanine aminotransferase ratio were higher, whereas BMI was lower in patients with ALD than in NAFLD (P<0.01). CONCLUSION The ANI scoring system may be used for the estimation of alcoholic origin of steatosis/steatohepatitis and may help in triaging patients for liver biopsy. ANI less than -0.66 indicates NAFLD, whereas ANI greater than -0.66 confirms the alcoholic etiology, but does not exclude the contribution of associated factors toward the development of fatty liver in a Serbian population.
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Affiliation(s)
- Ivana Cerović
- Department of Hepatology, Clinical Centre of Serbia, Institute for Digestive Diseases, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
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Mandegary A, Saeedi A, Eftekhari A, Montazeri V, Sharif E. Hepatoprotective effect of silyamarin in individuals chronically exposed to hydrogen sulfide; modulating influence of TNF-α cytokine genetic polymorphism. ACTA ACUST UNITED AC 2013; 21:28. [PMID: 23566372 PMCID: PMC3626872 DOI: 10.1186/2008-2231-21-28] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2012] [Accepted: 03/17/2013] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND THE PURPOSE OF THE STUDY Silymarin, a standardized extract of the milk thistle (Silybum marianum), is believed to exert some of its hepatoprotective effects though inhibition of free radicals and inflammation. In this study the effect of some pro- and anti-inflammatory cytokines and also antioxidant genes polymorphisms on the hepatoprotective effects of silymarin in the occupationally exposed individuals to hydrogen sulfide (H2S) in the sour natural gas refinery was investigated. METHODS We genotyped seven polymorphisms in six genes reported by others as modifiers of oxidative stress (NQO1, mEPXH1, GSTT1 and GSTM1) and inflammation (TNF-α and TGF-β1) for an association in effect of decreasing in liver function tests (LFTs). The LFTs of 77 sour gas refinery workers were measured before and after administration of silymarin (140 mg, three times per day for 1 month). RESULTS A significant reduction of blood AST, ALT and ALP was observed after 30 days of consumption (p < 0.001). The decreasing effect of silymarin on ALT in the subjects with high producer genotype (A allele carriers) was less than low producers. There were no significant associations between TGF-β1 and the studied genes of oxidative stress pathway and the effectiveness of silymarin. CONCLUSION This is the first report about the effectiveness of silymarin in the subjects exposed chronically to H2S. Meanwhile, the modulatory effect of TNF-α on the effectiveness of silymarin might be used for individualize therapy.
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Affiliation(s)
- Ali Mandegary
- Department of Pharmacology & Toxicology, School of Pharmacy and Pharmaceutics Research Center, Kerman University of Medical Sciences, Kerman, Iran.
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Nezi V, Deutsch M, Gazouli M, Alexopoulou A, Paparrigopoulos T, Liappas IA, Dourakis SP. Polymorphisms of the CD14 genes are associated with susceptibility to alcoholic liver disease in Greek patients. Alcohol Clin Exp Res 2013; 37:244-251. [PMID: 23009036 DOI: 10.1111/j.1530-0277.2012.01925.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2012] [Accepted: 07/06/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND The incidence and severity of alcoholic liver disease (ALD) in chronic drinkers has been found to correlate with some environmental factors and especially with the dose of alcohol consumption, but it is obvious that other parameters clearly contribute to individual alcohol susceptibility. Chronic ethanol exposure leads to continuous endotoxin-mediated Toll-like receptor-4 (TLR-4) and CD14 activation and subsequent cytokine release resulting in chronic inflammation with continued hepatocellular damage. Therefore, genetic studies of polymorphism in TLR-4 and CD14 genes seem to be appropriate in determining genetic susceptibility to ALD. Our aim is to evaluate in a series of Greek drinkers, the possible association of polymorphisms in the TLR-4 and CD14 genes with ALD. METHODS In 96 patients with ALD polymorphism of TLR-4 and CD14 genes were studied compared with 104 patients with cirrhosis of other etiology, 100 healthy subjects, and 50 patients with a history of alcohol abuse but without liver disease. RESULTS No association between ALD and the presence of the Asp299Gly and Thr399Ile polymorphisms in the TLR-4 gene could be documented in our patients. Regarding the CD14 -159 (C/T) genotypes, TT genotype and T allele were found to be overrepresented in alcoholic patients compared with patients with nonalcohol-induced liver disease and healthy controls. On the other side, when compared patients with ALD and patients with alcohol abuse and no liver disease, TT genotype was found to be significantly less frequent. There is no statistically significant association with the presence of the T allele and the severity of ALD, suggesting that CD14 polymorphism does not influence disease severity in advanced stages of the disease. CONCLUSIONS In our series in Greek patients with alcohol abuse and alcoholic cirrhosis, a significant negative association with the CD14 endotoxin receptor gene polymorphism (TT genotype) but not with the TLR-4 gene polymorphism was documented.
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Affiliation(s)
- Vasiliki Nezi
- Second Department of Internal Medicine , Hippokration General Hospital, University of Athens Medical School, Athens, Greece.
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Abstract
Activation of inflammatory signaling pathways is of central importance in the pathogenesis of alcoholic liver disease (ALD) and nonalcoholic steatohepatitis (NASH). Recent studies demonstrated that Toll-like receptors, the sensors of microbial and endogenous danger signals, are expressed and activated in innate immune cells as well as in parenchymal cells in the liver and thereby contribute to ALD and NASH. In this review, we emphasize the importance of gut-derived endotoxin and its recognition by TLR4 in the liver. The significance of TLR-induced intracellular signaling pathways and cytokine production as well as the contribution of individual cell types to the inflammation is evaluated. The contribution of TLR signaling to the induction of liver fibrosis and to the progression of liver pathology mediated by viral pathogens is reviewed in the context of ALD and NASH.
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Affiliation(s)
- Jan Petrasek
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
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Wu XD, Zeng K, Gong CS, Chen J, Chen YQ. Transforming growth factor-β genetic polymorphisms on development of liver cirrhosis in a meta-analysis. Mol Biol Rep 2012; 40:535-43. [PMID: 23104471 DOI: 10.1007/s11033-012-2090-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2012] [Accepted: 10/03/2012] [Indexed: 12/18/2022]
Abstract
Transforming growth factor-β (TGF-β) protein has been supposed to be a risk factor for liver cirrhosis; however, the associations between its genes (TGF-β -509C>T and +869T>C) and liver cirrhosis remained unclear. This study was to quantitatively analyze the correlations by using a meta-analysis. Pubmed, Embase, Wanfang databases were retrieved up to November 1st, 2011. Odds ratio (OR) and 95 % confidence interval (95 %CI) were used to demonstrate the strength of association, and P < 0.05 of Z test indicated statistical significance. Combined analyses were performed by using fixed or random-effect model, depending on between-study heterogeneity. Seven studies were for TGF-β -509C>T polymorphism, and eight studies were for +869T>C polymorphism. Combined results indicated that neither TGF-β -509C>T nor +869T>C polymorphisms were associated with risk of liver cirrhosis [OR (95 % CI): 0.79 (0.60-1.04) for CT vs. TT of -509C>T and 0.87 (0.68-1.12) for CT vs. CC of +869T>C], with no between-study heterogeneity. In addition, subgroups analyses still inferred that two polymorphisms were not associated with risk of liver cirrhosis for HBV-infected patients, Asians and for Population-based studies. This meta-analysis indicated that neither TGF-β -509C>T nor +869T>C polymorphisms were associated with risk of liver cirrhosis, regardless of HBV infection or not.
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Affiliation(s)
- Xiao-Dan Wu
- Department of Anesthesiology, Fujian Provincial Hospital, Fujian Provincial Clinical Medical College, Fujian Medical University, Fuzhou 350001, Fujian, China
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Roy N, Mukhopadhyay I, Das K, Pandit P, Majumder PP, Santra A, Datta S, Banerjee S, Chowdhury A. Genetic variants of TNFα, IL10, IL1β, CTLA4 and TGFβ1 modulate the indices of alcohol-induced liver injury in East Indian population. Gene 2012; 509:178-88. [PMID: 22902304 DOI: 10.1016/j.gene.2012.07.077] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Accepted: 07/31/2012] [Indexed: 02/06/2023]
Abstract
Alcohol induced liver disease or alcoholic liver disease (ALD), a complex trait, encompasses a gamut of pathophysiological alterations in the liver due to continuous exposure to a toxic amount of alcohol (more than 80 g per day). Of all chronic heavy drinkers, only 15-20% develops hepatitis or cirrhosis concomitantly or in succession. Several studies revealed that inter-individual as well as inter-ethnic genetic variation is one of the major factors that predispose to ALD. The role of genetic factors in ALD has long been sought for in ethnically distinct population groups. ALD is fast emerging as an important cause of chronic liver disease in India; even in populations such as "Bengalis" who were "culturally immune" earlier. While the genetic involvement in the pathogenesis of ALD is being sought for in different races, the complex pathophysiology of ALD as well as the knowledge of population level diversity of the relevant alcohol metabolizing and inflammatory pathways mandates the need for well designed studies of genetic factors in ethnically distinct population groups. An array of cytokines plays a critical role as mediators of injury, inflammation, fibrosis and cirrhosis in ALD. We, therefore, studied the association of polymorphisms in five relevant cytokine genes with "clinically significant" ALD in an ethnic "Bengali" population in Eastern India. Compared with "alcoholic" controls without liver disease (n=110), TNFα -238AA genotype, IL1β -511CC genotype, TGFβ1 -509CC genotype and IL10 -592AA genotype were significantly overrepresented in ALD patients (n=181; OR=2.4 and 95% CI 1.2-5.5, P(genotype)=0.042, P(allelic)=0.008; OR=2.7 and 95% CI 1.2-5.9, P(genotype)=0.018, P(allelic)=0.023; OR=4.7 and 95% CI 1.7-13.1, P(genotype)=0.003, P(allelic)=0.014; and OR=2.2 and 95% CI 1.1-4.8, P(genotype)=0.04, P(allelic)=0.039 respectively). Moreover a cumulative genetic risk analysis revealed a significant trend for developing ALD with an increase in the number of risk alleles on IL10 and TGFβ1 loci among alcoholics. The risk genotype of IL1β and TGFβ1 also influences the total bilirubin, albumin and alanine aminotransferase levels among alcoholic "Bengalis". The present study is the first case-control study from Eastern India that comprehensively identified polymorphic markers in TNFα, IL10, IL1β and TGFβ1 genes to be associated with ALD in the Bengali population, accentuating the significance of genetic factors in clinical expressions of ALD.
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Affiliation(s)
- Neelanjana Roy
- Centre for Liver Research, Institute of Post Graduate Medical Education & Research, Kolkata, India.
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Yang Z, Qi X, Wu Q, Li A, Xu P, Fan D. Lack of association between TNF-α gene promoter polymorphisms and pancreatitis: a meta-analysis. Gene 2012; 503:229-234. [PMID: 22579868 DOI: 10.1016/j.gene.2012.04.057] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2012] [Accepted: 04/18/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIMS Tumor necrosis factor alpha (TNF-α) is a major proinflammatory cytokine involved in the etiology of pancreatitis. The association between pancreatitis and the -308G>A and -238G>A polymorphisms in TNF-α gene has been analyzed in several studies, but results have been inconsistent. The purpose of this study was to integrate previous findings and explore whether these polymorphisms are associated with susceptibility and severity to pancreatitis. METHODS A meta-analysis was performed by searching PubMed, Cochrane Library, and ScienceDirect databases. Data were extracted using predefined form and odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS Our meta-analysis of a total of 1569 pancreatitis cases and 1330 control subjects from twelve published case-control studies for the -308G>A polymorphism (OR 0.98; 95% CI 0.83-1.17), and of 480 cases and 302 controls from four studies for the -238G>A polymorphism (OR 0.92; 95% CI 0.58-1.47) did not show any significant associations of susceptibility to pancreatitis with the variant GA+AA genotypes compared with the GG genotype. An association between severity of acute pancreatitis and -308G>A polymorphism was not found either (OR 0.93; 95% CI 0.69-1.24). CONCLUSION Polymorphisms in two sites of TNF-α gene promoter do not alter the risk of pancreatitis.
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Affiliation(s)
- Zhiping Yang
- Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
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Zhu L, Li X, Miao C. Lack of association between TLR4 Asp299Gly and Thr399Ile polymorphisms and sepsis susceptibility: A meta-analysis. Gene 2012; 501:213-8. [DOI: 10.1016/j.gene.2012.04.027] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2011] [Revised: 03/17/2012] [Accepted: 04/09/2012] [Indexed: 01/03/2023]
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Chen D, Liu F, Yang C, Liang X, Shang Q, He W, Wang Z. Association between the TPH1 A218C polymorphism and risk of mood disorders and alcohol dependence: evidence from the current studies. J Affect Disord 2012; 138:27-33. [PMID: 21601290 DOI: 10.1016/j.jad.2011.04.018] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2011] [Revised: 03/21/2011] [Accepted: 04/21/2011] [Indexed: 12/22/2022]
Abstract
BACKGROUND Several studies have assessed the association between genetic polymorphisms of tryptophan hydroxylase (TPH1) and risk of mood disorders and alcohol dependence, with controversial results. Our aim was to assess the association of TPH1 A218C polymorphism (rs1800532) with mood disorders, including major depressive disorder and bipolar disorder, and alcohol dependence by using meta-analysis. METHODS Data were collected from the related literatures published until November 25, 2010 from MEDLINE, EMBASE and ISI Web of Science databases, and meta-analysis stratified by ethnicity was performed in either fixed or random effect model as appropriate by using Stata Statistical Package (version 10.0). RESULTS Twenty-seven individual studies were included in the current study, among which, there were 9 studies for bipolar disorder, with 1951 cases and 2161 controls, 14 studies for major depressive disorder, with 2340 cases and 3204 controls, and 4 studies for alcohol dependence, with 601 cases and 711 controls. We found that in Caucasian population, the TPH1 218AA genotype was significantly associated with increased bipolar disorder risk (recessive comparison: OR, 1.42; Bonferroni-adjusted P=0.006; homozygote comparison: OR, 1.63; Bonferroni-adjusted P=0.072), and elevated alcohol dependence risk (recessive comparison: OR, 1.83; Bonferroni-adjusted P=0.012), while the association was not significant in Asian population. Moreover, the A218C polymorphism did not appear to have any effect on major depressive disorder risk either in Caucasians or in Asians. CONCLUSION The TPH1 A218C polymorphism is a potential biomarker for bipolar disorder and alcohol dependence risk in Caucasian population.
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Affiliation(s)
- Dingyan Chen
- Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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Marcos M, Pastor I, Chamorro AJ, Ciria-Abad S, González-Sarmiento R, Laso FJ. Meta-analysis: glutathione-S-transferase allelic variants are associated with alcoholic liver disease. Aliment Pharmacol Ther 2011; 34:1159-72. [PMID: 21967547 DOI: 10.1111/j.1365-2036.2011.04862.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Only a minority of alcoholics develop alcoholic liver disease (ALD) and allelic variants within genes encoding glutathione-S-transferases (GST) have been associated with ALD vulnerability with controversial results. AIM To assess the effects of GST polymorphisms on ALD by means of a genetic association study and meta-analysis. METHODS We retrieved published studies on the relationship between allelic variants within GST genes and ALD by means of electronic database search. A meta-analysis was conducted in a fixed or random effects model. Calculations of odds ratios (OR) and their confidence intervals (CI), tests for heterogeneity of the results and sensitivity analysis, have been performed. A genetic association study comparing GSTM1, GSTT1 and GSTP1 genotype distribution among 279 alcoholics with or without ALD and 144 controls was also performed. Results Fifteen previous studies were identified analysing the association of ALD with polymorphisms within GST genes. After meta-analysis, we found a significant association between the possession of the GSTM1 null allele and the presence of ALD (OR=1.43; 95% CI: 1.14, 1.78; P=0.002) among alcoholic patients. A significant association was also found for the possession of the GSTP1 Val/Val genotype and the presence of ALD (OR=2.04; 95% CI: 1.09, 3.80; P=0.03). CONCLUSIONS Our results suggest that, among alcoholics, carriers of GSTM1 null genetic variant or Val/Val genotype of Ile/Val GSTP1 polymorphism have an increased risk to suffer from alcoholic liver disease. The role of glutathione-S-transferase as a potential therapeutic target in alcoholic liver disease is reinforced.
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Affiliation(s)
- M Marcos
- Department of Internal Medicine, Alcoholism Unit, University Hospital of Salamanca, Salamanca, Spain.
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Chen D, Liu F, Shang Q, Song X, Miao X, Wang Z. Association between polymorphisms of DRD2 and DRD4 and opioid dependence: evidence from the current studies. Am J Med Genet B Neuropsychiatr Genet 2011; 156B:661-70. [PMID: 21714067 DOI: 10.1002/ajmg.b.31208] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2010] [Accepted: 05/26/2011] [Indexed: 11/10/2022]
Abstract
Several studies have assessed the association between genetic polymorphisms of DRD2 and DRD4 genes and opioid dependence risk, while the results were inconsistent. We performed a meta-analysis, including 6,846 opioid dependence cases and 4,187 controls from 22 individual studies, to evaluate the roles of four variants (DRD2 -141ins/delC, rs1799732; DRD2 311 Ser > Cys, rs1801028; DRD2-related TaqI A, rs1800497 and DRD4 exon III VNTR) in opioid dependence for the first time. We found that the -141delC polymorphism was significantly associated with increased risk of opioid dependence (homozygote comparison: odds ratios [OR], 2.71; 95% confidence interval [CI], 1.74-4.22; dominant comparison: OR, 1.27; 95% CI, 1.09-1.48). Similarly, the TaqI A1 polymorphism was also significantly increased opioid dependence risk (homozygote comparison: OR, 2.06; 95% CI, 1.25-3.42; dominant comparison: OR, 1.34; 95% CI, 1.08-1.67). Moreover, long allele (≥5-repeat) and 7-repeat allele of DRD4 exon III VNTR were found to be associated with significantly increased opioid dependence risk (OR, 1.50; 95% CI, 1.24-1.80 and OR, 1.57; 95%, 1.18-2.09, respectively). However, no association was detected between the DRD2 311 Ser > Cys polymorphism and opioid dependence. In conclusion, our results suggested that DRD2 -141ins/delC, DRD2-related TaqI A and DRD4 exon III VNTR polymorphisms might play important roles in the development of opioid dependence.
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Affiliation(s)
- Dingyan Chen
- Department of Epidemiology and Health Statistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, PR China
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Kebir O, Gorsane MA, Blecha L, Krebs MO, Reynaud M, Benyamina A. Association of inflammation genes with alcohol dependence/abuse: a systematic review and a meta-analysis. Eur Addict Res 2011; 17:146-53. [PMID: 21447951 DOI: 10.1159/000324849] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Accepted: 02/01/2011] [Indexed: 01/18/2023]
Abstract
The aim of the present work was to systematically review all association studies of inflammation genes with alcohol dependence/alcohol abuse (AD/AA) and to perform a meta-analysis. Odds ratios (ORs) were estimated by contrasting the ratio of counts of the 'high-risk' versus 'low-risk' alleles in AD/AA cases versus controls. Data reported in at least three published studies were available for four genetic polymorphisms [TNF-α-238 (rs361525, G/A); TNF-α-308 (rs1800629, G/A); IL-1RA (VNTR [86 bp]n); IL-10-592 (rs1800896, C/A)]. In total, nine meta-analyses were performed. Of these, only the TNF-α-238 polymorphism showed a significant association with AD/AA (OR=1.36, 95% CI: 1.05-1.76). This risk remained significant and increased slightly when we considered only patients with advanced alcohol-related liver disease (AALD) (OR=1.5, 95% CI: 1.13-1.98) but not when we considered only patients without AALD (OR=1.08, 95% CI: 0.5-2.35). Sensitivity analysis showed that this genetic association is derived from the AALD phenotype rather than from AD. Our approach is limited by our phenotype definition; some studies included chronic heavy drinkers (minimal daily consumption of 80 g for a minimal duration of 10 years) but without a standardized psychiatric assessment.
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Affiliation(s)
- Oussama Kebir
- INSERM, Laboratory of Pathophysiology of Psychiatric Diseases, Centre of Psychiatry and Neurosciences, U894, Paris, France
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Qin H, Liu B, Shi T, Liu Y, Sun Y, Ma Y. Tumour necrosis factor-alpha polymorphisms and hepatocellular carcinoma: a meta-analysis. J Int Med Res 2010; 38:760-8. [PMID: 20819413 DOI: 10.1177/147323001003800304] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The genetic basis of susceptibility to hepatocellular carcinoma (HCC) is poorly understood. To summarize the quantitative association between polymorphisms of the tumour necrosis factor-alpha (TNFA) gene and HCC, a meta-analysis of relevant studies was performed. Ten case-control studies involving 1421 HCC cases were identified from the Medline, Embase and Current Contents databases. Combined results based on all studies showed that patients with HCC had a significantly lower frequency of the TNFA gene polymorphism -308GG than healthy controls. When stratifying for race, results were similar among Asians and Caucasians. When comparing with hepatitis B virus infection cases, no statistical association was found. This meta-analysis suggests that TNFA -308GG gene polymorphism is associated with a modest decrease in the risk of HCC.
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Affiliation(s)
- H Qin
- Department of General Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
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Bao W, Song F, Li X, Rong S, Yang W, Wang D, Xu J, Fu J, Zhao Y, Liu L. Association between heme oxygenase-1 gene promoter polymorphisms and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol 2010; 172:631-6. [PMID: 20682519 DOI: 10.1093/aje/kwq162] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Several studies have recently focused on the association between heme oxygenase-1 (HMOX1) gene promoter polymorphisms and susceptibility to type 2 diabetes mellitus; however, results have been conflicting. This systematic Human Genome Epidemiology review and meta-analysis was undertaken to integrate previous findings and summarize the effect size of the association of HMOX1 gene promoter polymorphisms with susceptibility to type 2 diabetes. The authors retrieved all studies matched to search terms from the PubMed/MEDLINE, EMBASE, and ISI Web of Science databases that had been published through December 31, 2009. The articles were then checked independently by 2 investigators according to the eligibility and exclusion criteria. For all alleles and genotypes, odds ratios were pooled using either fixed-effects or random-effects models. An increased odds ratio for type 2 diabetes was observed in persons with the (GT)(n) L (long) allele as compared with those with the (GT)(n) S (short) allele (odds ratio = 1.12, 95% confidence interval: 1.02, 1.24; P = 0.02). Furthermore, the diabetes odds ratio for persons with the LL genotype, versus those with the SS genotype, was significantly increased (odds ratio = 1.25, 95% confidence interval: 1.04, 1.50; P = 0.02). Persons carrying longer (GT)(n) repeats in the HMOX1 gene promoter may have a higher risk of type 2 diabetes.
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Affiliation(s)
- Wei Bao
- Department of Nutrition and Food Hygiene and Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
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Medici V, M.Peerson J, Stabler SP, French SW, Gregory JF, Virata MC, Albanese A, Bowlus CL, Devaraj S, Panacek EA, Rahim N, Richards JR, Rossaro L, Halsted CH. Impaired homocysteine transsulfuration is an indicator of alcoholic liver disease. J Hepatol 2010; 53:551-7. [PMID: 20561703 PMCID: PMC2923260 DOI: 10.1016/j.jhep.2010.03.029] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2010] [Revised: 03/17/2010] [Accepted: 03/24/2010] [Indexed: 12/16/2022]
Abstract
BACKGROUND & AIMS Although abnormal hepatic methionine metabolism plays a central role in the pathogenesis of experimental alcoholic liver disease (ALD), its relationship to the risk and severity of clinical ALD is not known. The aim of this clinical study was to determine the relationship between serum levels of methionine metabolites in chronic alcoholics and the risk and pathological severity of ALD. METHODS Serum levels of liver function biochemical markers, vitamin B6, vitamin B12, folate, homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, cysteine, alpha-aminobutyrate, glycine, serine, and dimethylglycine were measured in 40 ALD patients, of whom 24 had liver biopsies, 26 were active drinkers without liver disease, and 28 were healthy subjects. RESULTS Serum homocysteine was elevated in all alcoholics, whereas ALD patients had low vitamin B6 with elevated cystathionine and decreased alpha-aminobutyrate/cystathionine ratios, consistent with decreased activity of vitamin B6 dependent cystathionase. The alpha-aminobutyrate/cystathionine ratio predicted the presence of ALD, while cystathionine correlated with the stage of fibrosis in all ALD patients. CONCLUSIONS The predictive role of the alpha-aminobutyrate/cystathionine ratio for the presence of ALD and the correlation between cystathionine serum levels with the severity of fibrosis point to the importance of the homocysteine transsulfuration pathway in ALD and may have important diagnostic and therapeutic implications.
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Affiliation(s)
- Valentina Medici
- Department of Internal Medicine, University of California Davis, Sacramento, CA 95817, USA.
| | - Janet M.Peerson
- Department of Nutrition, University of California Davis, Sacramento, CA
| | - Sally P. Stabler
- Department of Medicine, University of Colorado Health Sciences Center, Denver, CO
| | - Samuel W. French
- Department of Pathology, UCLA/Harbor Medical Center, Torrance, CA
| | - Jesse F. Gregory
- Food Science and Human Nutrition Department, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, FL
| | | | - Antony Albanese
- Gastroenterology Section, Sacramento Veterans Affairs Medical Center, Sacramento, CA
| | | | - Sridevi Devaraj
- Department of Pathology, University of California Davis, Sacramento, CA
| | - Edward A. Panacek
- Department of Emergency Medicine, University of California Davis, Sacramento, CA
| | - Nazir Rahim
- Department of Internal Medicine, University of California Davis, Sacramento, CA
| | - John R. Richards
- Department of Emergency Medicine, University of California Davis, Sacramento, CA
| | - Lorenzo Rossaro
- Department of Internal Medicine, University of California Davis, Sacramento, CA
| | - Charles H. Halsted
- Department of Internal Medicine, University of California Davis, Sacramento, CA,Department of Nutrition, University of California Davis, Sacramento, CA
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