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1
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Pérez-Hernández O, de la Paz-Estrello AM, Fernández-Alonso P, Martín-Navarro LG, Fernández-Rodríguez C, Durán-Castellón MDC, Vera-Delgado VE, González-Reimers E, Martín-González C. SIRS criteria versus qSOFA score in patients with severe alcohol-related hepatitis. Intern Emerg Med 2025; 20:395-401. [PMID: 39392538 DOI: 10.1007/s11739-024-03786-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 09/26/2024] [Indexed: 10/12/2024]
Abstract
Severe alcohol-related hepatitis (sAH) is a potentially life-threatening complication of alcohol-related liver disease. SIRS criteria have been related to disease severity and may be a prognostic factor. Recently, qSOFA has been shown to be more prognostically accurate than SIRS in other inflammatory conditions. To determine whether qSOFA is a better prognostic score than SIRS criteria in sAH. We included 62 consecutive patients admitted for sAH, defined by modified Maddrey DF ≥ 32. MELD-Na, SIRS criteria and qSOFA score were calculated. Survival at 180 days was assessed. Twenty-four patients (38.7%) died after 180 days. Three or more SIRS criteria and two or more qSOFA criteria were associated with 180-day mortality (LR = 12.09, p = 0.001; LR = 4.81, p = 0.028, respectively). Patients with MELD-Na >30 points died during follow-up more frequently (LR = 5.997; p = 0.014). SIRS respiratory criterion (B = 5.113; p = 0.023) and qSOFA respiratory criterion (B = 5.985; p = 0.05), bilirubin (>10 mg/dL; LR = 5.43, p = 0.006), creatinine (>1 mg/dL; B = 5.885, p = 0.015) and hyponatraemia (LR= 5.75, p = 0.018) were associated with mortality. Cox Regression model revealed that only SIRS and MELD-Na were independent prognostic factors. SIRS criteria seem to be more useful for patients with sAH, as well as MELD-Na. In contrast, qSOFA has no independent prognostic value in patients with sAH.
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Affiliation(s)
- Onán Pérez-Hernández
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain
| | - Alejandro Mario de la Paz-Estrello
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain
| | - Paula Fernández-Alonso
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain
| | - Loreto Giesela Martín-Navarro
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain
| | - Camino Fernández-Rodríguez
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain
| | - María Del Carmen Durán-Castellón
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain
| | - Víctor Eugenio Vera-Delgado
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain
| | - Emilio González-Reimers
- Departamento de Medicina Interna, Dermatología y Psiquiatría, Universidad de La Laguna, Servicio de Medicina Interna, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain
| | - Candelaria Martín-González
- Servicio de Medicina Interna, Complejo Hospitalario Universitario de Canarias, San Cristóbal de La Laguna, Santa Cruz de Tenerife, Canary Islands, Spain.
- Departamento de Medicina Interna, Dermatología y Psiquiatría, Universidad de La Laguna, Servicio de Medicina Interna, Hospital Universitario de Canarias, Tenerife, Canary Islands, Spain.
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Effect of Porcine Placental Extract Mixture on Alcohol-Induced Hepatotoxicity in Rats. Curr Issues Mol Biol 2022; 44:2029-2037. [PMID: 35678666 PMCID: PMC9164070 DOI: 10.3390/cimb44050137] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/28/2022] [Accepted: 04/29/2022] [Indexed: 11/18/2022] Open
Abstract
This study was conducted to examine the effect of porcine placenta extract mixture (pPEM, enzymatic/acidic extract = 1/3) on alcoholic hepatotoxicity after pPEM dosing with alcohol in rats. The experimental groups were normal, control, silymarin, three pPEM (590, 1771, and 2511 mg/kg/day, po), and silymarin (100 mg/kg/day, po) groups (n = 10). Alcoholic hepatotoxicity was caused by a liquid ethanol diet for 4 weeks. The effect of pPEM and silymarin on alcoholic hepatotoxicity was evaluated by serology, hepatic ADH and ALDH activities, and histopathological findings. After oral dosing with alcohol for 4 weeks, ALT and AST were significantly increased to 33.7 → 115.6 and 81.37 → 235.0 in the alcohol group, respectively. These levels were decreased significantly to 83.9 and 126.7 in the silymarin group and dose-dependently to 73.6–56.9 and 139.2–122.8 in all pPEM groups. Hepatic ADH and ALDH might have been increased in the control and not in the silymarin and pPEM groups for hepatic ADH. All pPEM groups exhibited no effects on hepatic ALDH except for the high pPEM group. Mild inflammation and fatty lesions were observed in the alcohol group and were attenuated in the silymarin and pPEM groups. As a results, the pPEM showed protective activities against alcoholic hepatotoxicity on the serological markers, hepatic ADH and ALDH, and pathological findings.
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3
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Ferraguti G, Terracina S, Petrella C, Greco A, Minni A, Lucarelli M, Agostinelli E, Ralli M, de Vincentiis M, Raponi G, Polimeni A, Ceccanti M, Caronti B, Di Certo MG, Barbato C, Mattia A, Tarani L, Fiore M. Alcohol and Head and Neck Cancer: Updates on the Role of Oxidative Stress, Genetic, Epigenetics, Oral Microbiota, Antioxidants, and Alkylating Agents. Antioxidants (Basel) 2022; 11:145. [PMID: 35052649 PMCID: PMC8773066 DOI: 10.3390/antiox11010145] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/27/2021] [Accepted: 01/04/2022] [Indexed: 02/06/2023] Open
Abstract
Head and neck cancer (HNC) concerns more than 890,000 patients worldwide annually and is associated with the advanced stage at presentation and heavy outcomes. Alcohol drinking, together with tobacco smoking, and human papillomavirus infection are the main recognized risk factors. The tumorigenesis of HNC represents an intricate sequential process that implicates a gradual acquisition of genetic and epigenetics alterations targeting crucial pathways regulating cell growth, motility, and stromal interactions. Tumor microenvironment and growth factors also play a major role in HNC. Alcohol toxicity is caused both directly by ethanol and indirectly by its metabolic products, with the involvement of the oral microbiota and oxidative stress; alcohol might enhance the exposure of epithelial cells to carcinogens, causing epigenetic modifications, DNA damage, and inaccurate DNA repair with the formation of DNA adducts. Long-term markers of alcohol consumption, especially those detected in the hair, may provide crucial information on the real alcohol drinking of HNC patients. Strategies for prevention could include food supplements as polyphenols, and alkylating drugs as therapy that play a key role in HNC management. Indeed, polyphenols throughout their antioxidant and anti-inflammatory actions may counteract or limit the toxic effect of alcohol whereas alkylating agents inhibiting cancer cells' growth could reduce the carcinogenic damage induced by alcohol. Despite the established association between alcohol and HNC, a concerning pattern of alcohol consumption in survivors of HNC has been shown. It is of primary importance to increase the awareness of cancer risks associated with alcohol consumption, both in oncologic patients and the general population, to provide advice for reducing HNC prevalence and complications.
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Affiliation(s)
- Giampiero Ferraguti
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (S.T.); (M.L.)
| | - Sergio Terracina
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (S.T.); (M.L.)
| | - Carla Petrella
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
| | - Antonio Greco
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Antonio Minni
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Marco Lucarelli
- Department of Experimental Medicine, Sapienza University of Rome, 00185 Rome, Italy; (G.F.); (S.T.); (M.L.)
| | - Enzo Agostinelli
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Massimo Ralli
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Marco de Vincentiis
- Department of Sense Organs, Sapienza University of Rome, 00185 Rome, Italy; (A.G.); (A.M.); (E.A.); (M.R.); (M.d.V.)
| | - Giammarco Raponi
- Department of Public Health and Infectious Diseases, Sapienza University of Rome, 00185 Rome, Italy;
| | - Antonella Polimeni
- Department of Odontostomatological and Maxillofacial Sciences, Sapienza University of Rome, 00185 Rome, Italy;
| | - Mauro Ceccanti
- SITAC, Società Italiana per il Trattamento dell’Alcolismo, 00184 Rome, Italy;
- SIFASD, Società Italiana Sindrome Feto-Alcolica, 00184 Rome, Italy
| | - Brunella Caronti
- Department of Human Neurosciences, Sapienza University of Rome, 00185 Rome, Italy;
| | - Maria Grazia Di Certo
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
| | - Christian Barbato
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
| | - Alessandro Mattia
- Ministero dell’Interno, Dipartimento della Pubblica Sicurezza, Direzione Centrale di Sanità, Centro di Ricerche e Laboratorio di Tossicologia Forense, 00185 Rome, Italy;
| | - Luigi Tarani
- Department of Pediatrics, Sapienza University Hospital of Rome, 00185 Rome, Italy;
| | - Marco Fiore
- Institute of Biochemistry and Cell Biology, IBBC—CNR, 000185 Rome, Italy; (C.P.); (M.G.D.C.); (C.B.)
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Pham TPT, Alou MT, Golden MH, Million M, Raoult D. Difference between kwashiorkor and marasmus: Comparative meta-analysis of pathogenic characteristics and implications for treatment. Microb Pathog 2021; 150:104702. [PMID: 33359074 DOI: 10.1016/j.micpath.2020.104702] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 12/04/2020] [Accepted: 12/08/2020] [Indexed: 12/11/2022]
Abstract
Kwashiorkor and marasmus are two clinical syndromes observed in severe acute malnutrition. In this review, we highlighted the differences between these two syndromes by reviewing the data comparing kwashiorkor and marasmus in literature, combined with recent microbiological findings and meta-analysis. Depletion of antioxidants, vitamins and minerals were more severe in kwashiorkor than marasmus. This was consistent with the severe and uncontrolled oxidative stress associated with the depletion of gut anaerobes and the relative proliferation of aerotolerant gut pathogens. This relative proliferation and invasion of gut microbes belonging to the aerotolerant Proteobacteria phylum and pathogens suggested a specific microbial process critical in the pathogenesis of kwashiorkor. Liver mitochondrial and peroxisomal dysfunction could be secondary to toxic microbial compounds produced in the gut such as ethanol, lipopolysaccharides and endotoxins produced by Proteobacteria, particularly Klebsiella pneumoniae, and aflatoxin produced by Aspergillus species. The gut-liver axis alteration is characterized by oedema and a fatty and enlarged liver and was associated with a dramatic depletion of methionine and glutathione, an excessive level of free circulating iron and frequent lethal bacteraemia by enteric pathogens. This was consistent with the fact that antibiotics improved survival only in children with kwashiorkor but not marasmus. The specific pathogenic characteristics of kwashiorkor identified in this review open new avenues to develop more targeted and effective treatments for both marasmus and/or kwashiorkor. Urgent correction of plasma glutathione depletion, alongside supply of specific essential amino acids, particularly methionine and cysteine, early detection of pathogens and an antibiotic more efficient than amoxicillin in supressing gut Proteobacteria including K. pneumoniae, and probiotics to restore the human gut anaerobic mature microbiota could save many more children with kwashiorkor.
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Affiliation(s)
- Thi-Phuong-Thao Pham
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France; IHU Méditerranée Infection, Marseille, France
| | - Maryam Tidjani Alou
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France; IHU Méditerranée Infection, Marseille, France
| | - Michael H Golden
- Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, Scotland, UK
| | - Matthieu Million
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France; IHU Méditerranée Infection, Marseille, France
| | - Didier Raoult
- Aix-Marseille Univ, IRD, APHM, MEPHI, Marseille, France; IHU Méditerranée Infection, Marseille, France.
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Alcohol as an early life stressor: Epigenetics, metabolic, neuroendocrine and neurobehavioral implications. Neurosci Biobehav Rev 2020; 118:654-668. [PMID: 32976915 DOI: 10.1016/j.neubiorev.2020.08.018] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/18/2020] [Accepted: 08/25/2020] [Indexed: 12/14/2022]
Abstract
Ethanol exposure during gestation is an early life stressor that profoundly dysregulates structure and functions of the embryonal nervous system, altering the cognitive and behavioral development. Such dysregulation is also achieved by epigenetic mechanisms, which, altering the chromatin structure, redraw the entire pattern of gene expression. In parallel, an oxidative stress response at the cellular level and a global upregulation of neuroendocrine stress response, regulated by the HPA axis, exist and persist in adulthood. This neurobehavioral framework matches those observed in other psychiatric diseases such as mood diseases, depression, autism; those early life stressing events, although probably triggered by specific and different epigenetic mechanisms, give rise to largely overlapping neurobehavioral phenotypes. An early diagnosis of prenatal alcohol exposure, using reliable markers of ethanol intake, together with a deeper understanding of the pathogenic mechanisms, some of them reversible by their nature, can offer a temporal "window" of intervention. Supplementing a mother's diet with protective and antioxidant substances in addition to supportive psychological therapies can protect newborns from being affected.
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6
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Antioxidant properties of plant polyphenols in the counteraction of alcohol-abuse induced damage: Impact on the Mediterranean diet. J Funct Foods 2020. [DOI: 10.1016/j.jff.2020.104012] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Fortilin potentiates the peroxidase activity of Peroxiredoxin-1 and protects against alcohol-induced liver damage in mice. Sci Rep 2016; 6:18701. [PMID: 26726832 PMCID: PMC4698670 DOI: 10.1038/srep18701] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2015] [Accepted: 11/24/2015] [Indexed: 01/06/2023] Open
Abstract
Fortilin, a pro-survival molecule, inhibits p53-induced apoptosis by binding to the
sequence-specific DNA-binding domain of the tumor suppressor protein and preventing
it from transcriptionally activating Bax. Intriguingly, fortilin protects cells
against ROS-induced cell death, independent of p53. The signaling pathway through
which fortilin protects cells against ROS-induced cell death, however, is unknown.
Here we report that fortilin physically interacts with the antioxidant enzyme
peroxiredoxin-1 (PRX1), protects it from proteasome-mediated degradation, and keeps
it enzymatically active by blocking its deactivating phosphorylation by Mst1, a
serine/threonine kinase. At the whole animal level, the liver-specific
overexpression of fortilin reduced PRX1 phosphorylation in the liver, enhanced PRX1
activity, and protected the transgenic animals against alcohol-induced,
ROS-mediated, liver damage. These data suggest the presence of a novel
oxidative-stress-handling pathway where the anti-p53 molecule fortilin augments the
peroxidase PRX1 by protecting it against degradation and inactivation of the enzyme.
Fortilin-PRX1 interaction in the liver could be clinically exploited further to
prevent acute alcohol-induced liver damage in humans.
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In Vivo Acute on Chronic Ethanol Effects in Liver: A Mouse Model Exhibiting Exacerbated Injury, Altered Metabolic and Epigenetic Responses. Biomolecules 2015; 5:3280-94. [PMID: 26610587 PMCID: PMC4693278 DOI: 10.3390/biom5043280] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Accepted: 11/17/2015] [Indexed: 01/06/2023] Open
Abstract
Chronic alcoholics who also binge drink (i.e., acute on chronic) are prone to an exacerbated liver injury but its mechanism is not understood. We therefore investigated the in vivo effects of chronic and binge ethanol ingestion and compared to chronic ethanol followed by three repeat binge ethanol on the liver of male C57/BL6 mice fed ethanol in liquid diet (4%) for four weeks followed by binge ethanol (intragastric administration, 3.5 g/kg body weight, three doses, 12h apart). Chronic followed by binge ethanol exacerbated fat accumulation, necrosis, decrease in hepatic SAM and SAM:SAH ratio, increase in adenosine levels, and elevated CYP2E1 levels. Histone H3 lysine acetylation (H3AcK9), dually modified phosphoacetylated histone H3 (H3AcK9/PS10), and phosphorylated H2AX increased after binge whereas phosphorylation of histone H3 ser 10 (H3S10) and H3 ser 28 (H3S28) increased after chronic ethanol-binge. Histone H3 lysine 4 and 9 dimethylation increased with a marked dimethylation in H3K9 in chronic ethanol binge group. Trimethylated histone H3 levels did not change. Nuclear levels of histone acetyl transferase GCN5 and histone deacetylase HDAC3 were elevated whereas phospho-CREB decreased in a distinctive manner. Taken together, acute on chronic ethanol ingestion caused amplification of liver injury and elicited characteristic profiles of histone modifications, metabolic alterations, and changes in nuclear protein levels. These findings demonstrate that chronic ethanol exposure renders liver more susceptible to repeat acute/binge ethanol induced acceleration of alcoholic liver disease.
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9
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Factor analysis and correlation between CIWA-Ar protocol and biochemical-hematic profile in patients with alcohol withdrawal syndrome. REVISTA MÉDICA DEL HOSPITAL GENERAL DE MÉXICO 2015. [DOI: 10.1016/j.hgmx.2015.06.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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10
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Chelakkot-Govindalayathil AL, Mifuji-Moroka R, D'Alessandro-Gabazza CN, Toda M, Matsuda Y, Gil-Bernabe P, Roeen Z, Yasuma T, Yano Y, Gabazza EC, Iwasa M, Takei Y. Protein S exacerbates alcoholic hepatitis by stimulating liver natural killer T cells. J Thromb Haemost 2015; 13:142-54. [PMID: 25399514 DOI: 10.1111/jth.12789] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2014] [Accepted: 11/05/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND Alcohol consumption is a major cause of liver injury but the mechanisms are not completely understood. Protein S (PS) is an anticoagulant glycoprotein with multiple functions. The role of PS in liver injury is unknown. OBJECTIVES This study investigated the role of PS in acute alcoholic hepatitis. METHODS A mouse overexpressing human PS (hPS-TG) was generated in which acute hepatitis was induced by intraperitoneal injection of ethanol. RESULTS The levels of serum liver enzymes and liver tissue inflammatory cytokines and the degree of hepatic steatosis were significantly increased in hPS-TG mice treated with ethanol compared with ethanol-treated wild type (WT) mice. Cell expansion, activation and inhibition of apoptosis were significantly augmented in natural killer T (NKT) cells from hPS-TG mice compared with WT mice. Liver mononuclear cells from hPS-TG mice express higher levels of inflammatory cytokines than those from WT mice after stimulation with a specific stimulant of NKT cells in vitro. In a co-culture system of hepatocytes and NKT cells, the effects of PS on ethanol-mediated cell injury were suppressed by a CD1d neutralizing antibody. Alcoholic liver injury was significantly improved in mice pre-treated with PS siRNA and anti-protein S antibody compared with control mice. Patients with alcoholic hepatitis showed significantly increased plasma PS levels and enhanced liver expression of PS and CD1d compared with controls. CONCLUSIONS The results of this study suggest that PS exacerbates acute alcoholic hepatitis by inhibiting apoptosis of activated NKT cells.
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MESH Headings
- Animals
- Antibodies, Neutralizing/pharmacology
- Antigens, CD1d/immunology
- Antigens, CD1d/metabolism
- Apoptosis
- Blood Proteins/genetics
- Blood Proteins/metabolism
- Case-Control Studies
- Cells, Cultured
- Coculture Techniques
- Disease Models, Animal
- Ethanol
- Fatty Liver, Alcoholic/immunology
- Fatty Liver, Alcoholic/metabolism
- Fatty Liver, Alcoholic/pathology
- Hepatitis, Alcoholic/genetics
- Hepatitis, Alcoholic/immunology
- Hepatitis, Alcoholic/metabolism
- Hepatitis, Alcoholic/pathology
- Hepatitis, Alcoholic/prevention & control
- Hepatocytes/immunology
- Hepatocytes/metabolism
- Hepatocytes/pathology
- Humans
- Inflammation Mediators/immunology
- Inflammation Mediators/metabolism
- Liver/immunology
- Liver/metabolism
- Liver/pathology
- Lymphocyte Activation
- Male
- Mice, Inbred C57BL
- Mice, Transgenic
- Natural Killer T-Cells/immunology
- Natural Killer T-Cells/metabolism
- Protein S/genetics
- Protein S/metabolism
- RNAi Therapeutics
- Severity of Illness Index
- Signal Transduction
- Up-Regulation
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12
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Lazaro R, Wu R, Lee S, Zhu NL, Chen CL, French SW, Xu J, Machida K, Tsukamoto H. Osteopontin deficiency does not prevent but promotes alcoholic neutrophilic hepatitis in mice. Hepatology 2015; 61:129-40. [PMID: 25132354 PMCID: PMC4280361 DOI: 10.1002/hep.27383] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Accepted: 08/14/2014] [Indexed: 12/13/2022]
Abstract
UNLABELLED Alcoholic hepatitis (AH) is a distinct spectrum of alcoholic liver disease (ALD) with intense neutrophilic (polymorphonuclear; PMN) inflammation and high mortality. Although a recent study implicates osteopontin (SPP1) in AH, SPP1 is also shown to have protective effects on experimental ALD. To address this unsettled question, we examined the effects of SPP1 deficiency in male mice given 40% calories derived from ad libitum consumption of the Western diet high in cholesterol and saturated fat and the rest from intragastric feeding of alcohol diet without or with weekly alcohol binge. Weekly binge in this new hybrid feeding model shifts chronic ASH with macrophage inflammation and perisinusoidal and pericellular fibrosis to AH in 57% (15 of 26) of mice, accompanied by inductions of chemokines (Spp1, Cxcl1, and interleukin [Il]-17a), progenitor genes (Cd133, Cd24, Nanog, and epithelial cell adhesion molecule), PMN infiltration, and clinical features of AH, such as hypoalbuminemia, bilirubinemia, and splenomegaly. SPP1 deficiency does not reduce AH incidence and inductions of progenitor and fibrogenic genes, but rather enhances the Il-17a induction and PMN infiltration in some mice. Furthermore, in the absence of SPP1, chronic ASH mice without weekly binge begin to develop AH. CONCLUSION These results suggest that SPP1 has a protective, rather than causal, role for experimental AH reproduced in our model.
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Affiliation(s)
- Raul Lazaro
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Raymond Wu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Sunyoung Lee
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Nian-Ling Zhu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Chia-Lin Chen
- Southern California Research Center for ALPD and Cirrhosis,Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
| | - Samuel W. French
- Southern California Research Center for ALPD and Cirrhosis,Harbor-UCLA Medical Center, Los Angeles, California, USA
| | - Jun Xu
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California
| | - Keigo Machida
- Southern California Research Center for ALPD and Cirrhosis,Department of Molecular Microbiology and Immunology, Keck School of Medicine of the University of Southern California
| | - Hidekazu Tsukamoto
- Southern California Research Center for ALPD and Cirrhosis,Department of Pathology, Keck School of Medicine of the University of Southern California,Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California, USA
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Streba LAM, Vere CC, Streba CT, Ciurea ME. Focus on alcoholic liver disease: from nosography to treatment. World J Gastroenterol 2014; 20:8040-7. [PMID: 25009375 PMCID: PMC4081674 DOI: 10.3748/wjg.v20.i25.8040] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/06/2014] [Accepted: 02/16/2014] [Indexed: 02/06/2023] Open
Abstract
Abusive alcohol intake currently ranks as a major cause of liver disease, and is associated with significant mortality worldwide. Alcoholic liver disease (ALD) generically defines liver abnormalities ranging from liver steatosis to the end-stages of disease such as liver cirrhosis. Information regarding the precise incidence and prevalence of ALD is still limited by a lack of large population-based studies and by the absence of large systematic reviews of all epidemiological data available. However, existing collected data show an overall increase in the number of alcohol abusers and alcohol-related liver disease. The burden exerted on medical systems worldwide is significant, with hospitalization and management costs rising constantly over the years. A great number of all cirrhosis-related deaths in Europe and a significant percentage worldwide are associated with alcohol consumption. The main possible risk factors for ALD are the amount and duration of alcohol abuse, patterns of drinking and the type of alcoholic beverage consumed. However, ALD does not progress to cirrhosis in all patients, therefore a series of additional factors are implicated. Even though insufficiently studied, genetic factors are generally regarded as highly important, and the presence of comorbidities and dietary habits seem to play a role in disease onset and progression. This lack of clear pathophysiological data further translates in the absence of definite treatment for ALD and shall prove challenging in the coming years. In this article, we aimed to briefly review epidemiologic data on the burden of ALD, risk factors, clinical and nosographic as well as therapeutic aspects of this disease. Without attempting to be exhaustive, this short topic highlight emphasizes each point and may serve as a general guidance tool in the complicated literature related to ALD.
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Aroor AR, Restrepo RJ, Kharbanda KK, Shukla SD. Epigenetic histone modifications in a clinically relevant rat model of chronic ethanol-binge-mediated liver injury. Hepatol Int 2014. [PMID: 26201320 DOI: 10.1007/s12072-014-9546-4] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
PURPOSE Ethanol binge augments liver injury after chronic ethanol consumption in humans, but the mechanism behind the enhanced liver injury by ethanol binge is not known. In this study we used a clinically relevant rat model in which liver injury is amplified by binge after chronic ethanol treatment and investigated the importance of histone modifications. METHODS Eight-week-old Sprague-Dawley rats were fed ethanol in a liquid diet for 4 weeks. Control rats were fed an isocaloric liquid diet. This was followed by three binge administrations of ethanol (intragastric 5 g/kg body weight, 12 h apart). In the control, ethanol was replaced by water. Four hours after the last binge administration, liver samples were analyzed for histone modifications and parameters of liver injury. RESULTS Chronic ethanol administration alone caused an increase in histone H3 ser10 and ser28 (H3S10 or S28) phosphorylation, and binge ethanol reduced their levels. Levels of dually modified phosphoacetylated histone H3 (H3AcK9/PS10) increased after acute binge ethanol and remained same after chronic ethanol binge. In contrast, histone H3 lysine-9 acetylation (H3AcK9) was not increased after chronic ethanol but increased significantly after acute binge and chronic ethanol binge. Increase in histone acetylation was accompanied by increased phospho-ERK1/2 in the nuclear extracts. Increased acetylation after chronic ethanol binge was also accompanied by increased protein levels of GCN5 histone acetyl transferase and a modest increase in HDAC3 in the nucleus. Histone lysine-9 dimethylation was significantly increased after chronic ethanol binge. Chronic ethanol binge also resulted in a decrease in the SAM:SAH ratio with a relative decrease of SAM levels and a corresponding increase in SAH levels. CONCLUSIONS Ethanol binge after chronic ethanol altered the profile of site-specific histone modifications and may underlie the mechanism of augmented liver injury by chronic-ethanol-binge-treated rats.
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Affiliation(s)
- Annayya R Aroor
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Ricardo J Restrepo
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA
| | - Kusum K Kharbanda
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE, 68105, USA
| | - Shivendra D Shukla
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO, 65212, USA.
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Singal AK, Kamath PS, Gores GJ, Shah VH. Alcoholic hepatitis: current challenges and future directions. Clin Gastroenterol Hepatol 2014; 12:555-64; quiz e31-2. [PMID: 23811249 PMCID: PMC3883924 DOI: 10.1016/j.cgh.2013.06.013] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2013] [Revised: 06/06/2013] [Accepted: 06/07/2013] [Indexed: 02/07/2023]
Abstract
Alcoholic hepatitis is a distinct clinical syndrome among people with chronic and active alcohol abuse, with a potential for 30%-40% mortality at 1 month among those with severe disease. Corticosteroids or pentoxifylline are the current pharmacologic treatment options, but they provide only about 50% survival benefit. These agents are recommended for patients with modified discriminant function (mDF) ≥ 32 or Model for End-Stage Liver Disease score ≥ 18. The Lille score is used to determine response to steroids. Currently, a minimum of 6 months of abstinence from alcohol use is required for patients to receive a liver transplant, a requirement that cannot be met by patients with severe alcoholic hepatitis nonresponsive to steroids (Lille score ≥ 0.45). Data are emerging on the benefit of liver transplantation in select patients with first episode of severe alcoholic hepatitis. This review also focuses on recent treatment trials in alcoholic hepatitis including liver transplantation and its associated controversies, as well as possible future targets and pharmacologic treatment options for patients with alcoholic hepatitis that are being pursued through upcoming consortium studies.
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Affiliation(s)
- Ashwani K Singal
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Gregory J Gores
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Vijay H Shah
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
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16
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Misra S, Sharma V, Srivastava AK. Bacterial Polysaccharides: An Overview. POLYSACCHARIDES 2014. [DOI: 10.1007/978-3-319-03751-6_68-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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17
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Warren KR, Murray MM. Alcoholic liver disease and pancreatitis: global health problems being addressed by the US National Institute on Alcohol Abuse and Alcoholism. J Gastroenterol Hepatol 2013; 28 Suppl 1:4-6. [PMID: 23855288 DOI: 10.1111/jgh.12246] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/20/2013] [Indexed: 12/13/2022]
Abstract
The review article summarizes the mission of the National Institute on Alcohol Abuse and Alcoholism (NIAAA) with focus on the NIAAA's current and future research version for alcoholic liver disease and alcoholic pancreatitis.
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Affiliation(s)
- Kenneth R Warren
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA.
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18
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Baykara B, Mıcılı SC, Tugyan K, Tekmen I, Bagriyanik HA, Sonmez U, Sonmez A, Oktay G, Yener N, Ozbal S. The protective effects of carnosine in alcohol-induced hepatic injury in rats. Toxicol Ind Health 2012; 30:25-32. [DOI: 10.1177/0748233712446722] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Consumption of alcohol leads to oxidative stress in liver by inducing lipid peroxidation. The aim of this study was to investigate the effects of carnosine (CAR) in alcohol-induced liver injury by biochemical and histomorphological evaluations. The rats were divided into four groups, namely, control group, alcohol (AL) group, CAR group and AL + CAR group. Three doses of ethanol (5 g/kg, 25% (v/v) in distilled water) were given by nasogastric catheter for twice-a-day. CAR (100 mg/kg) was given 1 h before the administration of ethanol using the same method. Levels of alanine aminotransferase, aspartate aminotransferase, myeloperoxidase and malondialdehyde were significantly increased in the AL group compared with control, CAR and AL + CAR groups. Glutathione level was significantly decreased in the AL group, while it was increased in the AL + CAR group. Immunoreactivity of caspase-3 and bax increased in the hepatocytes of AL group when compared with control and AL + CAR groups. Expression of bcl-2 was decreased in AL group than AL + CAR group. Under electron microscopy, dense mitochondria, accumulation of lipid, sinusoidal dilatation, vacuolization and decrease in the number of microvilli were observed in AL group, while these findings were markedly less in the AL + CAR group. In conclusion, pretreatment of CAR is effective for recovering biochemical alterations and morphologic damage in the liver of rats treated with ethanol.
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Affiliation(s)
- B Baykara
- School of Physical Therapy and Rehabilitation, Dokuz Eylul University, Balcova, Izmir, Turkey
| | - S Cilaker Mıcılı
- Department of Histology and Embryology, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - K Tugyan
- Department of Histology and Embryology, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - I Tekmen
- Department of Histology and Embryology, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - HA Bagriyanik
- Department of Histology and Embryology, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - U Sonmez
- Department of Histology and Embryology, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - A Sonmez
- Department of Physiology, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - G Oktay
- Department of Biochemistry, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - N Yener
- Department of Biochemistry, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
| | - S Ozbal
- Department of Histology and Embryology, Dokuz Eylul University Medical School, Balcova, Izmir, Turkey
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Aroor AR, Roy LJ, Restrepo RJ, Mooney BP, Shukla SD. A proteomic analysis of liver after ethanol binge in chronically ethanol treated rats. Proteome Sci 2012; 10:29. [PMID: 22545783 PMCID: PMC3504578 DOI: 10.1186/1477-5956-10-29] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 04/30/2012] [Indexed: 12/16/2022] Open
Abstract
Background Binge ethanol in rats after chronic ethanol exposure augments necrosis and steatosis in the liver. In this study, two-dimensional gel electrophoresis proteomic profiles of liver of control, chronic ethanol, control-binge, and chronic ethanol- binge were compared. Results The proteomic analysis identified changes in protein abundance among the groups. The levels of carbonic anhydrase 3 (CA3) were decreased after chronic ethanol and decreased further after chronic ethanol-binge. Ethanol binge alone in control rats had no effect on this protein suggesting its possible role in increased susceptibility to injury by binge after chonic ethanol treatment. A protein spot, in which both cytosolic isocitrate dehydrogenase (IDH1) and glutamine synthetase (GS) were identified, showed a small decrease after chronic ethanol binge but western blot demonstrated significant decrease only for glutamine synthetase in chronic ethanol treated rats. The level of gluathione S-transferase mu isoform (GSTM1) increased after chronic ethanol but was lower after chronic ethanol-binge compared to chronic ethanol treatment. The protein levels of the basic form of protein disulfide isomerase associated protein 3 (PDIA3) were significantly decreased and the acidic forms were increased after chronic ethanol- binge but not in chronic ethanol treated rats or ethanol binge in control rats. The significant changes in proteome profile in chronic ethanol binge were accompanied by a marked increase in liver injury as evidenced by enhanced steatosis, necrosis, increased 4-hydroxynonenal labeled proteins, CYP2E1 expression, and decreased histone H2AX phosphorylation. Conclusions Given the role of CA3, IDH1 and GST in oxidative stress; PDIA3 in protein quality control, apoptosis and DNA repair and decreased glutamine synthetase as a sensitive marker of pericentral liver injury this proteome study of chronic ethanol-binge rat model identifies these proteins for the first time as molecular targets with potential role in progression of liver injury by binge ethanol drinking.
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Affiliation(s)
- Annayya R Aroor
- Department of Medical Pharmacology & Physiology, University of Missouri, Columbia, MO 65212, USA.
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Korkusuz H, Keese D, Raschidi BA, Hübner F, Namgaladze D, Hintereder G, Hammerstingl R, Korkusuz Y, Mönch C, Vogl TJ. Detection of a fatty liver after binge drinking: correlation of MR-spectroscopy, DECT, biochemistry and histology in a rat model. Acad Radiol 2011; 18:1349-57. [PMID: 21889898 DOI: 10.1016/j.acra.2011.07.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Revised: 07/26/2011] [Accepted: 07/27/2011] [Indexed: 12/14/2022]
Abstract
RATIONALE AND OBJECTIVES The purpose of this study was to evaluate the possibility of detecting a fatty liver after binge drinking in an animal model using (1)H magnetic resonance spectroscopy ((1)H-MRS), dual-energy computed tomography (DECT), biochemistry, and the gold standard of histology. MATERIALS AND METHODS In 20 inbred female Lewis rats, an alcoholic fatty liver was induced; 20 rats served as controls. To simulate binge drinking, each rat was given a dose of 9.3 g/kg body weight 50% ethanol twice, with 24 hours between applications. Forty-eight hours after the first injection, DECT and (1)H-MRS were performed. Fat content as well as triglycerides were also determined histologically and biochemically, respectively. To assess specific liver enzymes, blood was drawn from the orbital venous plexus. RESULTS In all 20 animals in the experimental group, fatty livers were detected using (1)H-MRS, DECT, and biochemical and histologic analysis. The spectroscopic fat/water ratio and the biochemical determination were highly correlated (r = 0.892, P < .05). A significant correlation was found between (1)H-MRS and histologic analysis (r = 0.941, P < .001). Also, a positive linear correlation was found between the dual-energy computed tomographic density of ΔHU and the biochemical (r = 0.751, P < .05) and histologic (r = 0.786, P < .001) analyses. CONCLUSIONS Quantification of hepatic fat content on (1)H-MRS showed high correlation with histologic and biochemical steatosis determination. In comparison to DECT, it is more suitable to reflect the severity of acute fatty liver.
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Gramenzi A, Gitto S, Caputo F, Biselli M, Lorenzini S, Bernardi M, Andreone P. Liver transplantation for patients with alcoholic liver disease: an open question. Dig Liver Dis 2011; 43:843-9. [PMID: 21550324 DOI: 10.1016/j.dld.2011.03.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2010] [Revised: 03/08/2011] [Accepted: 03/27/2011] [Indexed: 12/11/2022]
Abstract
End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase. In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies.
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Affiliation(s)
- Annagiulia Gramenzi
- Department of Clinical Medicine, University of Bologna, Semeiotica Medica, S.Orsola-Malpighi Hospital, Bologna, Italy
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Aroor AR, Shukla SD. Binge ethanol intake in chronically exposed rat liver decreases LDL-receptor and increases angiotensinogen gene expression. World J Hepatol 2011; 3:250-5. [PMID: 21969878 PMCID: PMC3182283 DOI: 10.4254/wjh.v3.i9.250] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2011] [Revised: 07/06/2011] [Accepted: 08/10/2011] [Indexed: 02/06/2023] Open
Abstract
AIM To investigated the status of low-density lipoprotein (LDL)-receptor and angiotensionogen gene expression in rats treated chronically with ethanol followed by binge administration, a model that mimics the human scenario. METHODS Rats were chronically treated with ethanol in liquid diet for 4 wk followed by a single binge mode of ethanol administration (5 mg/kg body weight). Samples were processed 4 h after binge ethanol administration (chronic ethanol binge). Control rats were fed isocaloric diet. In the control for binge, ethanol was replaced by water. Expression of mRNA for angiotensinogen, c-fos and LDL-receptor, and nuclear accumulation of phospho-extracellular regulated kinases (ERK)1/2 and ERK1/2 protein were examined. RESULTS Binge ethanol administration in chronically treated rats caused increase in steatosis and necrosis. Chronic ethanol alone had negligible effect on mRNA levels of LDL-receptor, or on the levels of nuclear ERK1/2 and phospho-ERK1/2. But, chronic ethanol followed by binge caused a decrease in LDL-receptor mRNA, and also decreased the levels of ERK1/2 and phospho-ERK1/2 in the nuclear compartment. On the other hand, chronic ethanol-binge increased mRNA expression of angiotensinogen and c-fos. CONCLUSION Binge ethanol after chronic exposure, causes transcriptional dysregulation of LDL-receptor and angiotensinogen genes, both cardiovascular risk factors.
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Affiliation(s)
- Annayya R Aroor
- Annayya R Aroor, Shivendra D Shukla, Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, MO 65212, United States
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Aroor AR, Jackson DE, Shukla SD. Elevated activation of ERK1 and ERK2 accompany enhanced liver injury following alcohol binge in chronically ethanol-fed rats. Alcohol Clin Exp Res 2011; 35:2128-38. [PMID: 21790671 DOI: 10.1111/j.1530-0277.2011.01577.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Binge drinking after chronic ethanol consumption is one of the important factors contributing to the progression of steatosis to steatohepatitis. The molecular mechanisms of this effect remain poorly understood. We have therefore examined in rats the effect of single and repeat ethanol binge superimposed on chronic ethanol intake on liver injury, activation of mitogen-activated protein kinases (MAPKs), and gene expression. METHODS Rats were chronically treated with ethanol in liquid diet for 4 weeks followed by single ethanol binge (5 gm/kg body weight) or 3 similar repeated doses of ethanol. Serum alcohol and alanine amino transferase (ALT) levels were determined by enzymatic methods. Steatosis was assessed by histology and hepatic triglycerides. Activation of MAPK, 90S ribosomal kinase (RSK), and caspase 3 were evaluated by Western blot. Levels of mRNA for tumor necrosis factor alpha (TNFα), early growth response-1 (egr-1), and plasminogen activator inhibitor-1 (PAI-1) were measured by real-time qRT-PCR. RESULTS Chronic ethanol treatment resulted in mild steatosis and necrosis, whereas chronic ethanol followed by binge group exhibited marked steatosis and significant increase in necrosis. Chronic binge group also showed significant increase (compared with chronic ethanol alone) in the phosphorylation of extracellular regulated kinase 1 (ERK1), ERK2, and RSK. Phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK did not increase by the binge. Ethanol binge, after chronic ethanol intake, caused increase in mRNA for egr-1 and PAI-1, but not TNFα. CONCLUSIONS Chronic ethanol exposure increases the susceptibility of rat liver to increased injury by 1 or 3 repeat binge. Among other alterations, the activated levels of ERK1, and more so ERK2, were remarkably amplified by binge suggesting a role of these isotypes in the binge amplification of the injury. In contrast, p38 MAPK and JNK1/2 activities were not amplified. These binge-induced changes were also reflected in the increases in the RNA levels for egr-1 and PAI-1. This study offers chronic followed by repeat binge as a model for the study of progression of liver injury by ethanol and highlights the involvement of ERK1 and ERK2 isotypes in the amplification of liver injury by binge ethanol.
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Affiliation(s)
- Annayya R Aroor
- Department of Medical Pharmacology and Physiology, University of Missouri School of Medicine, Columbia, 65212, USA
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Basra S, Anand BS. Definition, epidemiology and magnitude of alcoholic hepatitis. World J Hepatol 2011; 3:108-13. [PMID: 21731902 PMCID: PMC3124876 DOI: 10.4254/wjh.v3.i5.108] [Citation(s) in RCA: 67] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 03/06/2011] [Accepted: 03/13/2011] [Indexed: 02/06/2023] Open
Abstract
Alcoholic liver disease (ALD) is a major cause of alcohol-related morbidity and mortality. Its presentation ranges from fatty liver to alcoholic hepatitis (AH), cirrhosis, and hepatocellular carcinoma. Although the amount and pattern of alcohol consumption is a well recognized predisposing factor for the development of serious liver pathology, environmental factors and the host's genetic make-up may also play significant roles that have not yet been entirely explored. Continuing alcohol consumption is a major factor that influences the survival of patients with AH. The presence of cirrhosis at presentation or its development on follow up is a major factor determining the outcome in the long run. This chapter deals with the epidemiology and magnitude of ALD in general and AH in particular.
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Affiliation(s)
- Sarpreet Basra
- Sarpreet Basra, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
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Basra G, Basra S, Parupudi S. Symptoms and signs of acute alcoholic hepatitis. World J Hepatol 2011; 3:118-20. [PMID: 21731904 PMCID: PMC3124878 DOI: 10.4254/wjh.v3.i5.118] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2010] [Revised: 03/08/2011] [Accepted: 03/15/2011] [Indexed: 02/06/2023] Open
Abstract
Although there is not one specific sign or symptom related to alcoholic hepatitis (AH), a constellation of symptoms and signs can help make the diagnosis of AH with reasonable accuracy. Documentation of chronic and active alcohol abuse is paramount in making a diagnosis of AH. Clinical presentation after abstinence for more than 3 m should raise doubts about the diagnosis of AH and dictate the need for considering other causes of liver disease, decompensation of alcoholic cirrhosis, sepsis and malignancy as the cause of patient's clinical profile.
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Affiliation(s)
- Gurjot Basra
- Gurjot Basra, Sarpreet Basra, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, United States
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Short-term and long-term vital outcomes of cirrhotic patients admitted to an intensive care unit. Eur J Gastroenterol Hepatol 2010; 22:1474-80. [PMID: 21389797 DOI: 10.1097/meg.0b013e32834059cd] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To evaluate short-term and long-term vital outcomes of cirrhotic patients admitted to a general ICU, to evaluate the prognostic value of severity scores and to identify risk factors associated with death. METHODS Observational retrospective single-center epidemiological study. All cirrhotic patients admitted to the ICU were eligible for the study. Clinical data, general ICU severity scores, and liver-specific severity scores were recorded. The mortality rate was analyzed during the stay in ICU, at day 28 and month 6 after admission. Risk factors for death were identified by univariate and multivariate analyses. RESULTS During the study period, 86 cirrhotic patients were admitted to the ICU. The in-ICU, day-28 and month-6 mortality rates were 37, 48, and 60%, respectively. In the multivariate analysis, mechanical ventilation, the prothrombin time, and the plasma albumin level on admission were associated with the in-ICU mortality, whereas only the plasma albumin level was associated with the 6-month mortality [odds ratio 0.80; 95% confidence interval (0.70-0.92)]. The Sequential Organ Failure Assessment score was more predictive than liver-specific scores for mortality in the ICU, but not at day 28 or month 6. CONCLUSION ICU admission should not be ruled out for patients with complicated cirrhosis. Although common in cirrhotic patients, low plasma albumin level was the only factor independently associated with short-term and long-term mortalities.
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Abstract
OBJECTIVES Data on temporal changes in alcoholic liver disease (ALD)-related mortality in the United States are lacking. This longitudinal assessment is important, given the divergent data on trends in worldwide ALD-related mortality, concerns for underestimation of mortality attributed to ALD in previous investigations, and shifting attention to hepatitis C virus (HCV)-related mortality. METHODS We analyzed mortality data compiled in the multiple cause-of-death public-use data file from the National Vital Statistics System from 1980 to 2003 using categorization by both International Classification of Diseases (ICD)-9 and ICD-10 systems. The main outcome measure was age- and sex-adjusted death rates attributable to ALD, HCV, or both (ALD/HCV) listed as immediate or underlying cause of death. RESULTS A total of 287,365 deaths were observed over the 24-year period. Age- and sex- adjusted incidence rates of ALD-related deaths decreased from 6.9/100,000 persons in 1980 to 4.4/100,000 persons by 2003. After introduction of HCV diagnostic testing, HCV-related liver mortality increased to 2.9/100,000 persons by 2003. Death rates for subjects with concomitant ALD/HCV rose to 0.2/100,000 persons by 1999 and then remained unchanged through 2003. Age-specific mortality related to ALD was highest in the ages of 45-64 years. Between 1980 and 2003, the age- and sex-adjusted ALD-related mortality (per 100,000 persons) decreased from 6.3 to 4.5 among Caucasians, 11.6 to 4.1 among African Americans, and 8.0 to 3.7 among the "other" race group. CONCLUSIONS Despite a decline in ALD-related mortality, the proportion of alcohol-related liver deaths is still considerably large and comparable in scope to that of HCV.
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Abstract
BACKGROUND Alcoholic hepatitis is a life-threatening disease, with an average mortality of approximately 40%. There is no widely accepted, effective treatment for alcoholic hepatitis. Pentoxifylline is used to treat alcoholic hepatitis, but there has been no systematic review to assess its effects. OBJECTIVES To assess the benefits and harms of pentoxifylline in alcoholic hepatitis. SEARCH STRATEGY The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, LILACS, clinicaltrials.gov, and full text searches were conducted until August 2009. Manufacturers and authors were contacted. SELECTION CRITERIA All randomised clinical trials of pentoxifylline in participants with alcoholic hepatitis compared to control were selected for inclusion. DATA COLLECTION AND ANALYSIS Two authors extracted data and evaluated the risk of bias. RevMan Analysis was used for statistical analysis of dichotomous data with risk ratio (RR) and of continuous data with mean difference (MD), both with 95% confidence intervals (CI). Trial sequential analysis (TSA) was also used for statistical analysis of dichotomous and continuous data in order to control for random error. Where data were only available from one trial, we used Fisher's exact test or Student's t-test. MAIN RESULTS Five trials, with a total of 336 randomised participants, were included. A total of 105 participants (31%) died. Of the five included trials, four (80%) had a high risk of bias. Meta-analysis using all five trials showed that pentoxifylline reduced mortality compared with control (RR 0.64; 95% CI 0.46 to 0.89). However, this result was not supported by trial sequential analysis, which adjusts for multiple testing on accumulating data. Furthermore, four of the five trials were judged to have a high risk of bias, thus risking an overestimated intervention effect. Meta-analysis showed that pentoxifylline reduced the hepatic-related mortality due to hepatorenal syndrome (RR 0.40; 95% CI 0.22 to 0.71), but trial sequential analysis did not support this result. Data from one trial suggests that pentoxifylline may increase the occurrence of serious and non-serious adverse events compared to control. AUTHORS' CONCLUSIONS The current available data may indicate a possible positive intervention effect of pentoxifylline on all-cause mortality and mortality due to hepatorenal syndrome, and conversely, an increase in serious and non-serious adverse events. However, the evidence is not firm; no conclusions can be drawn regarding whether pentoxifylline has a positive, negative, or neutral effect on participants with alcoholic hepatitis.
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Affiliation(s)
- Kate Whitfield
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Andrea Rambaldi
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Jørn Wetterslev
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University HospitalBlegdamsvej 9CopenhagenDenmarkDK‐2100
| | - Christian Gluud
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 3344, Rigshospitalet, Copenhagen University HospitalCochrane Hepato‐Biliary GroupBlegdamsvej 9CopenhagenDenmarkDK‐2100
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Abstract
The advent of liver transplantation has greatly improved the long-term survival of patients with decompensated cirrhosis, and surgery is now performed more frequently in patients with advanced liver disease. The estimation of perioperative mortality is limited by the retrospective nature of and biased patient selection in the available clinical studies. The overall experience is that, in patients with cirrhosis, use of the Child classification and Model for End-Stage Liver Disease (MELD) score provides a reasonably precise estimation of perioperative mortality. Careful preoperative preparation and monitoring to detect complications early in the postoperative course are essential to improve outcomes.
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Affiliation(s)
- Jacqueline G O'Leary
- Division of Hepatology, Department of Internal Medicine, Baylor University Medical Center, 4th Floor Roberts, 3500 Gaston Avenue, Dallas, TX 75246, USA
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Abstract
Alcohol abuse is a global problem due to the financial burden on society and the healthcare system. While the harmful health effects of chronic alcohol abuse are well established, more recent data suggest that acute alcohol consumption also affects human wellbeing. Thus, there is a need for research models in order to fully understand the effect of acute alcohol abuse on different body systems and organs. The present manuscript summarizes the interdisciplinary advantages and disadvantages of currently available human and non-human models of acute alcohol abuse, and identifies their suitability for biomedical research.
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Vonghia L, Leggio L, Ferrulli A, Bertini M, Gasbarrini G, Addolorato G. Acute alcohol intoxication. Eur J Intern Med 2008; 19:561-7. [PMID: 19046719 DOI: 10.1016/j.ejim.2007.06.033] [Citation(s) in RCA: 206] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2007] [Revised: 05/09/2007] [Accepted: 06/21/2007] [Indexed: 01/01/2023]
Abstract
Acute alcohol intoxication is a clinically harmful condition that usually follows the ingestion of a large amount of alcohol. Clinical manifestations are heterogeneous and involve different organs and apparatuses, with behavioral, cardiac, gastrointestinal, pulmonary, neurological, and metabolic effects. The management of an intoxicated patient occurs mainly in the emergency department and is aimed at stabilizing the clinical condition of the patient, depending on his/her clinical presentation. One specific drug that is useful in the treatment of acute alcohol intoxication is metadoxine, which is able to accelerate ethanol excretion. In patients presenting an acute alcohol intoxication, alcohol-related disorders should be detected so that the patient can be directed to an alcohol treatment unit, where a personalized, specific treatment can be established.
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Affiliation(s)
- Luisa Vonghia
- Institute of Internal Medicine, Catholic University of Rome, Italy
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Bhamidimarri RSK. Management of common problems in patients with chronic liver disease: a practical guide. Br J Hosp Med (Lond) 2008; 69:M92-5. [PMID: 18646417 DOI: 10.12968/hmed.2008.69.sup6.29640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Osburn WO, Yates MS, Dolan PD, Liby KT, Sporn MB, Taguchi K, Yamamoto M, Kensler TW. Genetic or pharmacologic amplification of nrf2 signaling inhibits acute inflammatory liver injury in mice. Toxicol Sci 2008; 104:218-27. [PMID: 18417483 PMCID: PMC2435415 DOI: 10.1093/toxsci/kfn079] [Citation(s) in RCA: 132] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Oxidative stress-mediated destruction of normal parenchymal cells during hepatic inflammatory responses contributes to the pathogenesis of immune-mediated hepatitis and is implicated in the progression of acute inflammatory liver injury to chronic inflammatory liver disease. The transcription factor NF-E2-related factor 2 (Nrf2) regulates the expression of a battery of antioxidative enzymes and Nrf2 signaling can be activated by small-molecule drugs that disrupt Keap1-mediated repression of Nrf2 signaling. Therefore, genetic and pharmacologic approaches were used to activate Nrf2 signaling to assess protection against inflammatory liver injury. Profound increases in indicators of cell death were observed in both Nrf2 wild-type (Nrf2-WT) mice and Nrf2-disrupted (Nrf2-KO) mice 24 h following intravenous injection of concanavalin A (12.5 mg/kg, ConA), a model for T cell-mediated acute inflammatory liver injury. However, hepatocyte-specific conditional Keap1 null (Alb-Cre:Keap1(flox/-), cKeap1-KO) mice with constitutively enhanced expression of Nrf2-regulated antioxidative genes as well as Nrf2-WT mice but not Nrf2-KO mice pretreated with three daily doses of a triterpenoid that potently activates Nrf2 (30 mumol/kg, cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl-imidazolide [CDDO-Im]) were highly resistant to ConA-mediated inflammatory liver injury. CDDO-Im pretreatment of both Nrf2-WT and Nrf2-KO mice resulted in equivalent suppression of serum proinflammatory soluble proteins suggesting that the hepatoprotection afforded by CDDO-Im pretreatment of Nrf2-WT mice but not Nrf2-KO mice was not due to suppression of systemic proinflammatory signaling, but instead was due to activation of Nrf2 signaling in the liver. Enhanced hepatic expression of Nrf2-regulated antioxidative genes inhibited inflammation-mediated oxidative stress, thereby preventing hepatocyte necrosis. Attenuation of hepatocyte death in cKeap1-KO mice and CDDO-Im pretreated Nrf2-WT mice resulted in decreased late-phase proinflammatory gene expression in the liver thereby diminishing the sustained influx of inflammatory cells initially stimulated by the ConA challenge. Taken together, these results clearly illustrate that targeted cytoprotection of hepatocytes through Nrf2 signaling during inflammation prevents the amplification of inflammatory responses in the liver.
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Affiliation(s)
- William O. Osburn
- Johns Hopkins University Bloomberg School of Public Health, Department of Environmental Health Sciences, Baltimore, MD
| | - Melinda S. Yates
- Johns Hopkins University School of Medicine, Department of Pharmacology and Molecular Sciences, Baltimore, MD
| | - Patrick D. Dolan
- Johns Hopkins University Bloomberg School of Public Health, Department of Environmental Health Sciences, Baltimore, MD
| | - Karen T. Liby
- Dartmouth Medical School, Department of Pharmacology and Toxicology, Hanover, NH
| | - Michael B. Sporn
- Dartmouth Medical School, Department of Pharmacology and Toxicology, Hanover, NH
| | - Keiko Taguchi
- Tohoku University Graduate School of Medicine and ERATO Environmental Response Project, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan
| | - Masayuki Yamamoto
- Tohoku University Graduate School of Medicine and ERATO Environmental Response Project, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan
| | - Thomas W. Kensler
- Johns Hopkins University Bloomberg School of Public Health, Department of Environmental Health Sciences, Baltimore, MD
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Li TK. Quantifying the risk for alcohol-use and alcohol-attributable health disorders: present findings and future research needs. J Gastroenterol Hepatol 2008; 23 Suppl 1:S2-8. [PMID: 18336658 DOI: 10.1111/j.1440-1746.2007.05298.x] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The aim of the present review was to: (i) highlight epidemiological and other studies that have generated important data on the harmful patterns of drinking that increase the risk for chronic diseases, including alcohol dependence, and on the mechanisms by which alcohol produces and, in some instances, may protect against damage; and (ii) discuss a conceptual basis for quantifying risk criteria for alcohol-induced chronic disease based on the quantity, frequency, and pattern of drinking. The relationship between heavy drinking and risk for adverse health conditions such as alcoholic liver disease (ALD), dementia, and alcohol dependence is well known. However, not everyone who drinks chronically develops ALD or dementia, and the major risk factors for disease development and the mechanisms by which this occurs have remained unclear. Large-scale, general population-based studies have provided the evidence by which quantifying the frequency of a pattern of high-risk drinking can be related directly to risk and the severity of alcohol dependence. Cellular and molecular biology studies have identified the major pathways of alcohol metabolism and how genetics and the environment can interact in some individuals to further increase the risk of organ damage. Extant databases should allow scientists and clinicians jointly to develop the framework for quantifying the drinking patterns that increase the risk of alcohol-induced organ pathologies, to develop clinical practice guidelines, such as those used to diagnose other common complex diseases (e.g. diabetes and hypertension), and to propose future studies for refining such guidelines. Attention must be paid to comorbid conditions such as hepatitis B and C infections, HIV, obesity, and environmental exposures other than alcohol. Developing trait and state biomarkers is critical to the process of discovery and to fulfilling the promise of personalized medicine.
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Affiliation(s)
- Ting-Kai Li
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland 20892-9304, USA.
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Hollander JM, Mechanick JI. Complementary and Alternative Medicine and the Management of the Metabolic Syndrome. ACTA ACUST UNITED AC 2008; 108:495-509. [DOI: 10.1016/j.jada.2007.12.007] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2007] [Indexed: 01/06/2023]
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Zakhari S, Li TK. Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease. Hepatology 2007; 46:2032-9. [PMID: 18046720 DOI: 10.1002/hep.22010] [Citation(s) in RCA: 233] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
UNLABELLED More than 70% of alcohol is consumed by 10% of the population in the United States. Implicit in this statistic is that tremendous variation in the pattern of drinking (quantity, frequency, and duration) exists among alcohol consumers. Individuals who are binge or chronic drinkers will have different health outcomes than social drinkers. Therefore, knowing the pattern of drinking will shed light on how severely individuals are alcohol-dependent and on the extent of liver damage. Thus, these parameters assume particular relevance for the treatment-providing physician. Genetic factors contribute substantially to differences in alcohol metabolism. Variations in the activities of the alcohol-metabolizing enzymes, cytosolic alcohol dehydrogenase and mitochondrial aldehyde dehydrogenase, in part determine blood alcohol concentration, thereby contributing to the predisposition to becoming alcohol-dependent and to susceptibility to alcohol-induced liver damage. Chronic alcohol consumption induces cytochrome P450 2E1, a microsomal enzyme that metabolizes alcohol at high concentrations and also metabolizes medications such as acetaminophen and protease inhibitors. Alcohol metabolism changes the redox state of the liver, which leads to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. The quantity and frequency of alcohol consumption severely impact the liver in the presence of comorbid conditions such as infection with hepatitis B or C and/or human immunodeficiency virus, type 2 diabetes, hemochromatosis, or obesity and thus have implications with respect to the extent of injury and response to medications. CONCLUSION Knowledge of the relationships between the quantity, frequency, and patterns of drinking and alcoholic liver disease is limited. A better understanding of these relationships will guide hepatologists in managing alcoholic liver disease.
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Affiliation(s)
- Samir Zakhari
- National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892-9304, USA.
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Abstract
PURPOSE OF REVIEW This review aims to acquaint the reader with advances in 2006 in the epidemiology, genetics, detection, pathogenesis and treatment of alcoholic liver disease. RECENT FINDINGS Important discoveries have been made in pathogenesis and mechanism of disease, with great emphasis on the many pathways leading to oxidative stress, and the novel mechanism of endoplasmic reticulum stress that is proving to be important in the pathogenesis of many liver diseases. The reliability of ethyl glucuronide and other biomarkers for the detection of alcohol abuse is being better established. There have been no treatment advances for alcoholic liver disease but, on balance, steroids are still favored for carefully selected patients with alcoholic hepatitis. Many compounds tested in rodents may now be available for consideration for clinical trials. Criteria for patient selection and refusal for liver transplantation are being established but the 6 months abstinence rule still holds. SUMMARY Insights are being made into the pathogenesis of alcoholic liver disease but safe and effective therapies for both alcoholic hepatitis and alcoholic cirrhosis have yet to be discovered.
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Affiliation(s)
- Adrian Reuben
- Liver Service, Division of Gastroenterology and Hepatology, And Liver Transplant Program, Medical University of South Carolina, Charleston, South Carolina, USA.
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