PDF herunterladen
Semin Liver Dis 2009; 29(2): 211-221
DOI: 10.1055/s-0029-1214376
© Thieme Medical Publishers

Alcohol and Liver Fibrosis

Francisco Javier Cubero1 [*] , Raquel Urtasun1 [*] , Natalia Nieto1
  • 1Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, New York, New York
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
22. April 2009 (online)

    Lizenzen und Reprints

ABSTRACT

Alcoholic liver disease involves significant crosstalk among intracellular signaling events in the liver. Overall, inflammatory and innate immune responses in Kupffer cells due to elevated gut-derived plasma endotoxin levels, increased reactive oxygen species-induced damage, and profibrogenic factors such as acetaldehyde or lipid peroxidation products contribute to activation of hepatic stellate cells, the key cell type involved in liver fibrosis. Using in vitro and in vivo approaches, there has been great progress in our understanding of the mechanisms leading to liver fibrosis: potential biomarkers of fibrosis have been identified, and several candidate targets for antifibrotic drugs have been elucidated.

KEYWORDS

Kupffer cells - hepatic stellate cells - alcohol - extracellular matrix protein - fibrosis

REFERENCES

  • 1 Heidelbaugh J J, Bruderly M. Cirrhosis and chronic liver failure: part I. Diagnosis and evaluation.  Am Fam Physician. 2006;  74(5) 756-762
    PubMedGoogle Scholar
  • 2 Bataller R, Brenner D A. Liver fibrosis.  J Clin Invest. 2005;  115(2) 209-218
    CrossrefPubMedGoogle Scholar
  • 3 Bataller R, Sancho-Bru P, Gines P, Brenner D A. Liver fibrogenesis: a new role for the renin-angiotensin system.  Antioxid Redox Signal. 2005;  7(9–10) 1346-1355
    CrossrefPubMedGoogle Scholar
  • 4 Bataller R, North K E, Brenner D A. Genetic polymorphisms and the progression of liver fibrosis: a critical appraisal.  Hepatology. 2003;  37(3) 493-503
    CrossrefPubMedGoogle Scholar
  • 5 Wood M J, Powell L W, Ramm G A. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis.  Blood. 2008;  111(9) 4456-4462
    CrossrefPubMedGoogle Scholar
  • 6 Stickel F, Hoehn B, Schuppan D, Seitz H K. Review article: nutritional therapy in alcoholic liver disease.  Aliment Pharmacol Ther. 2003;  18(4) 357-373
    CrossrefPubMedGoogle Scholar
  • 7 D'Alfonso S, Richiardi P M. A polymorphic variation in a putative regulation box of the TNFA promoter region.  Immunogenetics. 1994;  39(2) 150-154
    PubMedGoogle Scholar
  • 8 Lieber C S. ALCOHOL: its metabolism and interaction with nutrients.  Annu Rev Nutr. 2000;  20 395-430
    CrossrefPubMedGoogle Scholar
  • 9 Lieber C S. Alcohol and the liver: metabolism of alcohol and its role in hepatic and extrahepatic diseases.  Mt Sinai J Med. 2000;  67(1) 84-94
    PubMedGoogle Scholar
  • 10 Lieber C S. Prevention and treatment of liver fibrosis based on pathogenesis.  Alcohol Clin Exp Res. 1999;  23(5) 944-949
    PubMedGoogle Scholar
  • 11 Lieber C S. Microsomal ethanol-oxidizing system (MEOS): the first 30 years (1968–1998)—a review.  Alcohol Clin Exp Res. 1999;  23(6) 991-1007
    PubMedGoogle Scholar
  • 12 Mello T, Ceni E, Surrenti C, Galli A. Alcohol induced hepatic fibrosis: role of acetaldehyde.  Mol Aspects Med. 2008;  29(1–2) 17-21
    CrossrefPubMedGoogle Scholar
  • 13 Jones A W. Ethanol metabolism in patients with liver cirrhosis.  J Clin Forensic Med. 2000;  7(1) 48-51
    CrossrefPubMedGoogle Scholar
  • 14 Jones B E, Czaja III M J. Intracellular signaling in response to toxic liver injury.  Am J Physiol. 1998;  275(5 Pt 1) G874-G878
    PubMedGoogle Scholar
  • 15 Cubero F J, Nieto N. Kupffer cells and alcoholic liver disease.  Rev Esp Enferm Dig. 2006;  98(6) 460-472
    PubMedGoogle Scholar
  • 16 Nagy L E. Molecular aspects of alcohol metabolism: transcription factors involved in early ethanol-induced liver injury.  Annu Rev Nutr. 2004;  24 55-78
    CrossrefPubMedGoogle Scholar
  • 17 Cederbaum A I. CYP2E1–biochemical and toxicological aspects and role in alcohol-induced liver injury.  Mt Sinai J Med. 2006;  73(4) 657-672
    PubMedGoogle Scholar
  • 18 Soderberg B L, Salem R O, Best C A, Cluette-Brown J E, Laposata M. Fatty acid ethyl esters. Ethanol metabolites that reflect ethanol intake.  Am J Clin Pathol. 2003;  119(suppl) S94-S99
    PubMedGoogle Scholar
  • 19 Sleyster E C, Knook D L. Relation between localization and function of rat liver Kupffer cells.  Lab Invest. 1982;  47(5) 484-490
    PubMedGoogle Scholar
  • 20 Eriksson C J. The role of acetaldehyde in the actions of alcohol (update 2000).  Alcohol Clin Exp Res. 2001;  25(suppl) 15S-32S
    PubMedGoogle Scholar
  • 21 Franks N P, Lieb W R. Molecular and cellular mechanisms of general anaesthesia.  Nature. 1994;  367(6464) 607-614
    CrossrefPubMedGoogle Scholar
  • 22 Lieber C S. Mechanism of ethanol induced hepatic injury.  Pharmacol Ther. 1990;  46(1) 1-41
    CrossrefPubMedGoogle Scholar
  • 23 Osna N A, Donohue Jr T M. Implication of altered proteasome function in alcoholic liver injury.  World J Gastroenterol. 2007;  13(37) 4931-4937
    PubMedGoogle Scholar
  • 24 Cubero F J, Nieto N. Ethanol and arachidonic acid synergize to activate Kupffer cells and modulate the fibrogenic response via TNF-a, GSH, and TGF-β dependent mechanisms.  Hepatology. 2008;  48(6) 2027-2039
    CrossrefPubMedGoogle Scholar
  • 25 Paradis V, Kollinger M, Fabre M, Holstege A, Poynard T, Bedossa P. In situ detection of lipid peroxidation by-products in chronic liver diseases.  Hepatology. 1997;  26(1) 135-142
    CrossrefPubMedGoogle Scholar
  • 26 Racanelli V, Rehermann B. The liver as an immunological organ.  Hepatology. 2006;  43(suppl 1) S54-S62
    CrossrefPubMedGoogle Scholar
  • 27 Hines I N, Wheeler M D. Recent advances in alcoholic liver disease III. Role of the innate immune response in alcoholic hepatitis.  Am J Physiol Gastrointest Liver Physiol. 2004;  287(2) G310-G314
    CrossrefPubMedGoogle Scholar
  • 28 Wheeler M D, Kono H, Yin M et al.. The role of Kupffer cell oxidant production in early ethanol-induced liver disease.  Free Radic Biol Med. 2001;  31(12) 1544-1549
    CrossrefPubMedGoogle Scholar
  • 29 Thurman II R G. Alcoholic liver injury involves activation of Kupffer cells by endotoxin.  Am J Physiol. 1998;  275(4 Pt 1) G605-G611
    PubMedGoogle Scholar
  • 30 Thakur V, Pritchard M T, McMullen M R, Wang Q, Nagy L E. Chronic ethanol feeding increases activation of NADPH oxidase by lipopolysaccharide in rat Kupffer cells: role of increased reactive oxygen in LPS-stimulated ERK1/2 activation and TNF-alpha production.  J Leukoc Biol. 2006;  79(6) 1348-1356
    CrossrefPubMedGoogle Scholar
  • 31 Osna N A, White R L, Todero S et al.. Ethanol-induced oxidative stress suppresses generation of peptides for antigen presentation by hepatoma cells.  Hepatology. 2007;  45(1) 53-56
    CrossrefPubMedGoogle Scholar
  • 32 Nieto N. Oxidative-stress and IL-6 mediate the fibrogenic effects of [corrected] Kupffer cells on stellate cells.  Hepatology. 2006;  44(6) 1487-1501
    CrossrefPubMedGoogle Scholar
  • 33 Siegmund S V, Dooley S, Brenner D A. Molecular mechanisms of alcohol-induced hepatic fibrosis.  Dig Dis. 2005;  23(3–4) 264-274
    CrossrefPubMedGoogle Scholar
  • 34 Siegmund S V, Brenner D A. Molecular pathogenesis of alcohol-induced hepatic fibrosis.  Alcohol Clin Exp Res. 2005;  29(11, Suppl) 102S-109S
    CrossrefPubMedGoogle Scholar
  • 35 Thurman R G, Bradford B U, Iimuro Y et al.. Role of Kupffer cells, endotoxin and free radicals in hepatotoxicity due to prolonged alcohol consumption: studies in female and male rats.  J Nutr. 1997;  127(5, Suppl) 903S-906S
    PubMedGoogle Scholar
  • 36 Nanji A A, Mendenhall C L, French S W. Beef fat prevents alcoholic liver disease in the rat.  Alcohol Clin Exp Res. 1989;  13(1) 15-19
    CrossrefPubMedGoogle Scholar
  • 37 Tsukamoto H, French S W, Reidelberger R D, Largman C. Cyclical pattern of blood alcohol levels during continuous intragastric ethanol infusion in rats.  Alcohol Clin Exp Res. 1985;  9(1) 31-37
    CrossrefPubMedGoogle Scholar
  • 38 Seki E, De Minicis S, Osterreicher C H et al.. TLR4 enhances TGF-beta signaling and hepatic fibrosis.  Nat Med. 2007;  13(11) 1324-1332
    CrossrefPubMedGoogle Scholar
  • 39 Spitzer J A, Spitzer J J. Lipopolysaccharide tolerance and ethanol modulate hepatic nitric oxide production in a gender-dependent manner.  Alcohol. 2000;  21(1) 27-35
    CrossrefPubMedGoogle Scholar
  • 40 Mathison J C, Virca G D, Wolfson E, Tobias P S, Glaser K, Ulevitch R J. Adaptation to bacterial lipopolysaccharide controls lipopolysaccharide-induced tumor necrosis factor production in rabbit macrophages.  J Clin Invest. 1990;  85(4) 1108-1118
    CrossrefPubMedGoogle Scholar
  • 41 Beck I T, Dinda P K. Acute exposure of small intestine to ethanol: effects on morphology and function.  Dig Dis Sci. 1981;  26(9) 817-838
    CrossrefPubMedGoogle Scholar
  • 42 Persson J O, Terelius Y, Ingelman-Sundberg M. Cytochrome P-450-dependent formation of reactive oxygen radicals: isozyme-specific inhibition of P-450-mediated reduction of oxygen and carbon tetrachloride.  Xenobiotica. 1990;  20(9) 887-900
    CrossrefPubMedGoogle Scholar
  • 43 Enomoto N, Schemmer P, Ikejima K et al.. Long-term alcohol exposure changes sensitivity of rat Kupffer cells to lipopolysaccharide.  Alcohol Clin Exp Res. 2001;  25(9) 1360-1367
    CrossrefPubMedGoogle Scholar
  • 44 Nagy L E. Recent insights into the role of the innate immune system in the development of alcoholic liver disease.  Exp Biol Med (Maywood). 2003;  228(8) 882-890
    PubMedGoogle Scholar
  • 45 Mandrekar P. Signaling mechanisms in alcoholic liver injury: role of transcription factors, kinases and heat shock proteins.  World J Gastroenterol. 2007;  13(37) 4979-4985
    PubMedGoogle Scholar
  • 46 Bedossa P, Paradis V. Liver extracellular matrix in health and disease.  J Pathol. 2003;  200(4) 504-515
    PubMedGoogle Scholar
  • 47 Lin X Z, Horng M H, Sun Y N, Shiesh S C, Chow N H, Guo X Z. Computer morphometry for quantitative measurement of liver fibrosis: comparison with Knodell's score, colorimetry and conventional description reports.  J Gastroenterol Hepatol. 1998;  13(1) 75-80
    CrossrefPubMedGoogle Scholar
  • 48 Rojkind M, Giambrone M A, Biempica L. Collagen types in normal and cirrhotic liver.  Gastroenterology. 1979;  76(4) 710-719
    PubMedGoogle Scholar
  • 49 Martinez-Hernandez A. The hepatic extracellular matrix. I. Electron immunohistochemical studies in normal rat liver.  Lab Invest. 1984;  51(1) 57-74
    PubMedGoogle Scholar
  • 50 Pick-Kober K H, Munker D, Gressner A M. Fibronectin is synthesized as an acute phase reactant in rat hepatocytes.  J Clin Chem Clin Biochem. 1986;  24(8) 521-528
    PubMedGoogle Scholar
  • 51 Guyot C, Lepreux S, Combe C et al.. Hepatic fibrosis and cirrhosis: the (myo)fibroblastic cell subpopulations involved.  Int J Biochem Cell Biol. 2006;  38(2) 135-151
    PubMedGoogle Scholar
  • 52 McGuire R F, Bissell D M, Boyles J, Roll F J. Role of extracellular matrix in regulating fenestrations of sinusoidal endothelial cells isolated from normal rat liver.  Hepatology. 1992;  15(6) 989-997
    CrossrefPubMedGoogle Scholar
  • 53 Somasundaram R, Schuppan D. Type I, II, III, IV, V, and VI collagens serve as extracellular ligands for the isoforms of platelet-derived growth factor (AA, BB, and AB).  J Biol Chem. 1996;  271(43) 26884-26891
    CrossrefPubMedGoogle Scholar
  • 54 Benyon R C, Arthur M J. Extracellular matrix degradation and the role of hepatic stellate cells.  Semin Liver Dis. 2001;  21(3) 373-384
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 55 Hemmann S, Graf J, Roderfeld M, Roeb E. Expression of MMPs and TIMPs in liver fibrosis - a systematic review with special emphasis on anti-fibrotic strategies.  J Hepatol. 2007;  46(5) 955-975
    CrossrefPubMedGoogle Scholar
  • 56 Irigoyen J P, Munoz-Canoves P, Montero L, Koziczak M, Nagamine Y. The plasminogen activator system: biology and regulation.  Cell Mol Life Sci. 1999;  56(1–2) 104-132
    CrossrefPubMedGoogle Scholar
  • 57 Suzuki K, Enghild J J, Morodomi T, Salvesen G, Nagase H. Mechanisms of activation of tissue procollagenase by matrix metalloproteinase 3 (stromelysin).  Biochemistry. 1990;  29(44) 10261-10270
    CrossrefPubMedGoogle Scholar
  • 58 Urtasun R, Cubero F J, Vera M, Nieto N. Reactive nitrogen species switch on early extracellular matrix remodeling via induction of MMP-1 and TNF-a.  Gastroenterology. 2009;  136(4) 1410-1422
    CrossrefPubMedGoogle Scholar
  • 59 Friedman S L. Mechanisms of hepatic fibrogenesis.  Gastroenterology. 2008;  134(6) 1655-1669
    CrossrefPubMedGoogle Scholar
  • 60 D'Armiento J, DiColandrea T, Dalal S S et al.. Collagenase expression in transgenic mouse skin causes hyperkeratosis and acanthosis and increases susceptibility to tumorigenesis.  Mol Cell Biol. 1995;  15(10) 5732-5739
    PubMedGoogle Scholar
  • 61 Kwon O S, Lim D Y, Kwon K A et al.. Clinical usefulness of plasma activities of gelatinase (matrix metalloproteinase-2 and 9) in chronic liver disease.  Taehan Kan Hakhoe Chi. 2003;  9(3) 222-230
    PubMedGoogle Scholar
  • 62 Apte S S, Fukai N, Beier D R, Olsen B R. The matrix metalloproteinase-14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP-2 gene during mouse embryogenesis.  J Biol Chem. 1997;  272(41) 25511-25517
    CrossrefPubMedGoogle Scholar
  • 63 Ueberham E, Low R, Ueberham U, Schonig K, Bujard H, Gebhardt R. Conditional tetracycline-regulated expression of TGF-beta1 in liver of transgenic mice leads to reversible intermediary fibrosis.  Hepatology. 2003;  37(5) 1067-1078
    CrossrefPubMedGoogle Scholar
  • 64 Holmbeck K, Bianco P, Caterina J et al.. MT1-MMP-deficient mice develop dwarfism, osteopenia, arthritis, and connective tissue disease due to inadequate collagen turnover.  Cell. 1999;  99(1) 81-92
    CrossrefPubMedGoogle Scholar
  • 65 Safadi R, Friedman S L. Hepatic fibrosis–role of hepatic stellate cell activation.  MedGenMed. 2002;  4(3) 27
    PubMedGoogle Scholar
  • 66 Moreira R K. Hepatic stellate cells and liver fibrosis.  Arch Pathol Lab Med. 2007;  131(11) 1728-1734
    PubMedGoogle Scholar
  • 67 Morini S, Carotti S, Carpino G et al.. GFAP expression in the liver as an early marker of stellate cells activation.  Ital J Anat Embryol. 2005;  110(4) 193-207
    PubMedGoogle Scholar
  • 68 Eng F J, Friedman S L, Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex.  Am J Physiol Gastrointest Liver Physiol. 2000;  279(1) G7-G11
    PubMedGoogle Scholar
  • 69 Cassiman D, Van Pelt J, De Vos R et al.. Synaptophysin: a novel marker for human and rat hepatic stellate cells.  Am J Pathol. 1999;  155(6) 1831-1839
    PubMedGoogle Scholar
  • 70 Ghyselinck N B, Bavik C, Sapin V et al.. Cellular retinol-binding protein I is essential for vitamin A homeostasis.  EMBO J. 1999;  18(18) 4903-4914
    CrossrefPubMedGoogle Scholar
  • 71 Friedman S L, Roll F J, Boyles J, Bissell D M. Hepatic lipocytes: the principal collagen-producing cells of normal rat liver.  Proc Natl Acad Sci U S A. 1985;  82(24) 8681-8685
    CrossrefPubMedGoogle Scholar
  • 72 Yoshiji H, Kuriyama S, Noguchi R et al.. Amelioration of liver fibrogenesis by dual inhibition of PDGF and TGF-beta with a combination of imatinib mesylate and ACE inhibitor in rats.  Int J Mol Med. 2006;  17(5) 899-904
    PubMedGoogle Scholar
  • 73 Urtasun R, Nieto N. Hepatic stellate cells and oxidative stress.  Rev Esp Enferm Dig. 2007;  99(4) 223-230
    PubMedGoogle Scholar
  • 74 Nieto N, Rojkind M. Repeated whiskey binges promote liver injury in rats fed a choline-deficient diet.  J Hepatol. 2007;  46(2) 330-339
    CrossrefPubMedGoogle Scholar
  • 75 Friedman S L. Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver.  Physiol Rev. 2008;  88(1) 125-172
    CrossrefPubMedGoogle Scholar
  • 76 Henderson N C, Iredale J P. Liver fibrosis: cellular mechanisms of progression and resolution.  Clin Sci (Lond). 2007;  112(5) 265-280
    CrossrefPubMedGoogle Scholar
  • 77 Iredale J P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ.  J Clin Invest. 2007;  117(3) 539-548
    CrossrefPubMedGoogle Scholar
  • 78 Kisseleva T, Uchinami H, Feirt N et al.. Bone marrow-derived fibrocytes participate in pathogenesis of liver fibrosis.  J Hepatol. 2006;  45(3) 429-438
    CrossrefPubMedGoogle Scholar
  • 79 Pinzani M, Rombouts K. Liver fibrosis: from the bench to clinical targets.  Dig Liver Dis. 2004;  36(4) 231-242
    CrossrefPubMedGoogle Scholar
  • 80 Iwano M, Plieth D, Danoff T M, Xue C, Okada H, Neilson E G. Evidence that fibroblasts derive from epithelium during tissue fibrosis.  J Clin Invest. 2002;  110(3) 341-350
    CrossrefPubMedGoogle Scholar
  • 81 Kalluri R, Neilson E G. Epithelial-mesenchymal transition and its implications for fibrosis.  J Clin Invest. 2003;  112(12) 1776-1784
    CrossrefPubMedGoogle Scholar
  • 82 Krizhanovsky V, Yon M, Dickins R A et al.. Senescence of activated stellate cells limits liver fibrosis.  Cell. 2008;  134(4) 657-667
    CrossrefPubMedGoogle Scholar
  • 83 Murphy F R, Issa R, Zhou X et al.. Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis.  J Biol Chem. 2002;  277(13) 11069-11076
    CrossrefPubMedGoogle Scholar
  • 84 Guyot C, Combe C, Balabaud C, Biolas-Sage P, Desmouliere A. Fibrogenic cell fate during fibrotic tissue remodelling observed in rat and human cultured liver slices.  J Hepatol. 2007;  46(1) 142-150
    CrossrefPubMedGoogle Scholar
  • 85 Issa R, Williams E, Trim N et al.. Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors.  Gut. 2001;  48(4) 548-557
    CrossrefPubMedGoogle Scholar
  • 86 Iredale J P. Tissue inhibitors of metalloproteinases in liver fibrosis.  Int J Biochem Cell Biol. 1997;  29(1) 43-54
    CrossrefPubMedGoogle Scholar
  • 87 Roeb E, Graeve L, Hoffmann R, Decker K, Edwards D R, Heinrich P C. Regulation of tissue inhibitor of metalloproteinases-1 gene expression by cytokines and dexamethasone in rat hepatocyte primary cultures.  Hepatology. 1993;  18(6) 1437-1442
    CrossrefPubMedGoogle Scholar
  • 88 Roderfeld M, Geier A, Dietrich C G et al.. Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase-1 expression and up-regulates matrix metalloproteinase-9 in toxic liver injury.  Liver Int. 2006;  26(5) 579-586
    CrossrefPubMedGoogle Scholar
  • 89 Arendt E, Ueberham U, Bittner R, Gebhardt R, Ueberham E. Enhanced matrix degradation after withdrawal of TGF-beta1 triggers hepatocytes from apoptosis to proliferation and regeneration.  Cell Prolif. 2005;  38(5) 287-299
    CrossrefPubMedGoogle Scholar
  • 90 Wynn T A. Cellular and molecular mechanisms of fibrosis.  J Pathol. 2008;  214(2) 199-210
    CrossrefPubMedGoogle Scholar
  • 91 Marra F, Aleffi S, Bertolani C, Petrai I, Vizzutti F. Adipokines and liver fibrosis.  Eur Rev Med Pharmacol Sci. 2005;  9(5) 279-284
    PubMedGoogle Scholar
  • 92 Bataller R, Sancho-Bru P, Gines P et al.. Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II.  Gastroenterology. 2003;  125(1) 117-125
    CrossrefPubMedGoogle Scholar
  • 93 De Minicis S, Brenner D A. Oxidative stress in alcoholic liver disease: role of NADPH oxidase complex.  J Gastroenterol Hepatol. 2008;  23(Suppl 1) S98-S103
    CrossrefPubMedGoogle Scholar
  • 94 De Minicis S, Bataller R, Brenner D A. NADPH oxidase in the liver: defensive, offensive, or fibrogenic?.  Gastroenterology. 2006;  131(1) 272-275
    CrossrefPubMedGoogle Scholar
  • 95 Bataller R, Schwabe R F, Choi Y H et al.. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis.  J Clin Invest. 2003;  112(9) 1383-1394
    PubMedGoogle Scholar
  • 96 Bertolani C, Marra F. The role of adipokines in liver fibrosis.  Pathophysiology. 2008;  15(2) 91-101
    CrossrefPubMedGoogle Scholar
  • 97 Diehl A M. Liver disease in alcohol abusers: clinical perspective.  Alcohol. 2002;  27(1) 7-11
    CrossrefPubMedGoogle Scholar
  • 98 Diehl A M. Nonalcoholic steatosis and steatohepatitis IV. Nonalcoholic fatty liver disease abnormalities in macrophage function and cytokines.  Am J Physiol Gastrointest Liver Physiol. 2002;  282(1) G1-G5
    CrossrefPubMedGoogle Scholar
  • 99 Rahmouni K, Haynes W G. Endothelial effects of leptin: implications in health and diseases.  Curr Diab Rep. 2005;  5(4) 260-266
    CrossrefPubMedGoogle Scholar
  • 100 Saxena N K, Titus M A, Ding X et al.. Leptin as a novel profibrogenic cytokine in hepatic stellate cells: mitogenesis and inhibition of apoptosis mediated by extracellular regulated kinase (Erk) and Akt phosphorylation.  FASEB J. 2004;  18(13) 1612-1614
    PubMedGoogle Scholar
  • 101 Aleffi S, Petrai I, Bertolani C et al.. Upregulation of proinflammatory and proangiogenic cytokines by leptin in human hepatic stellate cells.  Hepatology. 2005;  42(6) 1339-1348
    CrossrefPubMedGoogle Scholar
  • 102 Marra F, Aleffi S, Bertolani C, Petrai I, Vizzutti F. Review article: the pathogenesis of fibrosis in non-alcoholic steatohepatitis.  Aliment Pharmacol Ther. 2005;  22(suppl 2) 44-47
    CrossrefPubMedGoogle Scholar
  • 103 Zeng M D, Li Y M, Chen C W et al.. Guidelines for the diagnosis and treatment of alcoholic liver disease.  J Dig Dis. 2008;  9(2) 113-116
    CrossrefPubMedGoogle Scholar
  • 104 Huwart L, Sempoux C, Salameh N et al.. Liver fibrosis: noninvasive assessment with MR elastography versus aspartate aminotransferase-to-platelet ratio index.  Radiology. 2007;  245(2) 458-466
    CrossrefPubMedGoogle Scholar
  • 105 Manning D S, Afdhal N H. Diagnosis and quantitation of fibrosis.  Gastroenterology. 2008;  134(6) 1670-1681
    CrossrefPubMedGoogle Scholar
  • 106 Marsano L S, Mendez C, Hill D, Barve S, McClain C J. Diagnosis and treatment of alcoholic liver disease and its complications.  Alcohol Res Health. 2003;  27(3) 247-256
    PubMedGoogle Scholar
  • 107 Yin M, Talwalkar J A, Glaser K J et al.. Assessment of hepatic fibrosis with magnetic resonance elastography.  Clin Gastroenterol Hepatol. 2007;  5(10) 1207-1213
    CrossrefPubMedGoogle Scholar
  • 108 Powell Jr W J, Klatskin G. Duration of survival in patients with Laennec's cirrhosis. Influence of alcohol withdrawal, and possible effects of recent changes in general management of the disease.  Am J Med. 1968;  44(3) 406-420
    CrossrefPubMedGoogle Scholar
  • 109 Day C P. Treatment of alcoholic liver disease.  Liver Transpl. 2007;  13(suppl 2) S69-S75
    CrossrefPubMedGoogle Scholar
  • 110 McCullough A J, O'Connor J F. Alcoholic liver disease: proposed recommendations for the American College of Gastroenterology.  Am J Gastroenterol. 1998;  93(11) 2022-2036
    CrossrefPubMedGoogle Scholar
  • 111 Kershenobich D, Vargas F, Garcia-Tsao G, Perez Tamayo R, Gent M, Rojkind M. Colchicine in the treatment of cirrhosis of the liver.  N Engl J Med. 1988;  318(26) 1709-1713
    PubMedGoogle Scholar
  • 112 Rodriguez L, Cerbon-Ambriz J, Munoz M L. Effects of colchicine and colchiceine in a biochemical model of liver injury and fibrosis.  Arch Med Res. 1998;  29(2) 109-116
    PubMedGoogle Scholar
  • 113 Zois C D, Baltayiannis G H, Karayiannis P, Tsianos E V. Systematic review: hepatic fibrosis—regression with therapy.  Aliment Pharmacol Ther. 2008;  28 1175-1187
    CrossrefPubMedGoogle Scholar
  • 114 Lu S C, Gukovsky I, Lugea A et al.. Role of S-adenosylmethionine in two experimental models of pancreatitis.  FASEB J. 2003;  17(1) 56-58
    PubMedGoogle Scholar
  • 115 Lieber C S. Role of oxidative stress and antioxidant therapy in alcoholic and nonalcoholic liver diseases.  Adv Pharmacol. 1997;  38 601-628
    PubMedGoogle Scholar
  • 116 Harrison S A, Torgerson S, Hayashi P, Ward J, Schenker S. Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis.  Am J Gastroenterol. 2003;  98(11) 2485-2490
    CrossrefPubMedGoogle Scholar
  • 117 Bedossa P, Paradis V. Approaches for treatment of liver fibrosis in chronic hepatitis C.  Clin Liver Dis. 2003;  7(1) 195-210
    CrossrefPubMedGoogle Scholar
  • 118 Naveau S, Chollet-Martin S, Dharancy S et al.. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.  Hepatology. 2004;  39(5) 1390-1397
    CrossrefPubMedGoogle Scholar
  • 119 Liu X, Hu H, Yin J Q. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis.  Liver Int. 2006;  26(1) 8-22
    CrossrefPubMedGoogle Scholar
  • 120 Nakamura T, Sakata R, Ueno T, Sata M, Ueno H. Inhibition of transforming growth factor beta prevents progression of liver fibrosis and enhances hepatocyte regeneration in dimethylnitrosamine-treated rats.  Hepatology. 2000;  32(2) 247-255
    CrossrefPubMedGoogle Scholar
  • 121 Hall P. Factors influencing individual susceptibility to alcoholic liver disease: pathology and pathogenesis. In: Alcoholic Liver Disease. 2nd ed. London; Edward Arnold 1995: 299-316
    Google Scholar
  • 122 Nanji A A, Jui L T, French S W. Effect of chronic carbon monoxide exposure on experimental alcoholic liver injury in rats.  Life Sci. 1989;  45(10) 885-890
    CrossrefPubMedGoogle Scholar
  • 123 French S W, Benson N C, Sun P S. Centrilobular liver necrosis induced by hypoxia in chronic ethanol-fed rats.  Hepatology. 1984;  4(5) 912-917
    CrossrefPubMedGoogle Scholar
  • 124 Nanji A A, Jokelainen K, Fotouhinia M et al.. Increased severity of alcoholic liver injury in female rats: role of oxidative stress, endotoxin, and chemokines.  Am J Physiol Gastrointest Liver Physiol. 2001;  281(6) G1348-G1356
    PubMedGoogle Scholar
  • 125 Nanji A A, Tsukamoto H, French S W. Relationship between fatty liver and subsequent development of necrosis, inflammation and fibrosis in experimental alcoholic liver disease.  Exp Mol Pathol. 1989;  51(2) 141-148
    CrossrefPubMedGoogle Scholar
  • 126 Lieber C S, DeCarli L M. Liquid diet technique of ethanol administration: 1989 update.  Alcohol Alcohol. 1989;  24(3) 197-211
    PubMedGoogle Scholar
  • 127 Lieber C S. Pathogenesis of hepatic steatosis.  Gastroenterology. 1963;  45 760-764
    PubMedGoogle Scholar
  • 128 Popper H, Lieber C S. Histogenesis of alcoholic fibrosis and cirrhosis in the baboon.  Am J Pathol. 1980;  98(3) 695-716
    PubMedGoogle Scholar
  • 129 French S W. Intragastric ethanol infusion model for cellular and molecular studies of alcoholic liver disease.  J Biomed Sci. 2001;  8(1) 20-27
    CrossrefPubMedGoogle Scholar
  • 130 Tsukamoto H, French S W. Evolution of intragastric ethanol infusion model.  Alcohol. 1993;  10(6) 437-441
    CrossrefPubMedGoogle Scholar
  • 131 Gentry-Nielsen M J, Preheim L C, Lyman K N, McDonough K H, Potter B J. Use of rat models to mimic alterations in iron homeostasis during human alcohol abuse and cirrhosis.  Alcohol. 2001;  23(2) 71-81
    CrossrefPubMedGoogle Scholar
  • 132 French S W, Tsukamoto H. Animal models for alcoholic liver disease.  Hepatology. 1989;  10(5) 898-899
    CrossrefPubMedGoogle Scholar
  • 133 Hansen J, Skausig O B. Antabus in alcohol-induced liver damage.  Ugeskr Laeger. 1994;  156(30) 4368-4369
    PubMedGoogle Scholar
  • 134 Hasumura Y, Teschke R, Lieber C S. Increased carbon tetrachloride hepatotoxicity, and its mechanism, after chronic ethanol consumption.  Gastroenterology. 1974;  66(3) 415-422
    PubMedGoogle Scholar
  • 135 Kostrubsky V E, Szakacs J G, Jeffery E H et al.. Protection of ethanol-mediated acetaminophen hepatotoxicity by triacetyloleandomycin, a specific inhibitor of CYP3A.  Ann Clin Lab Sci. 1997;  27(1) 57-62
    PubMedGoogle Scholar
  • 136 Lindros K O, Stowell L, Vaananen H et al.. Uninterrupted prolonged ethanol oxidation as a main pathogenetic factor of alcoholic liver damage: evidence from a new liquid diet animal model.  Liver. 1983;  3(2) 79-91
    PubMedGoogle Scholar
  • 137 Lyman R L, Sheehan G, Tinoco J. Phosphatidylethanolamine metabolism in rats fed a low methionine, choline-deficient diet.  Lipids. 1973;  8(2) 71-79
    CrossrefPubMedGoogle Scholar

0 Both authors contributed equally to this review.

Natalia NietoPh.D. 

Department of Medicine, Division of Liver Diseases, Mount Sinai School of Medicine, Box 1123, 1425 Madison Avenue

Room 11-76, New York, NY 10029

eMail: natalia.nieto@mssm.edu