Chapter 12.2
Ethanol Metabolism and Pathogenesis of Alcoholic Liver Injury
Stephen F. Stewart,
Chris P. Day,
Stephen F. Stewart
Search for more papers by this authorChris P. Day
Search for more papers by this authorStephen F. Stewart,
Chris P. Day,
Stephen F. Stewart
Search for more papers by this authorChris P. Day
Search for more papers by this authorBook Editor(s):Juan Rodés MD,
Jean-Pierre Benhamou MD,
Andres T. Blei MD,
Jürg Reichen MD,
Mario Rizzetto MD,
Juan Rodés MD
Director General, Hospital Clinic; Professor of Medicine, University of Barcelona, Barcelona, Spain
Search for more papers by this authorJean-Pierre Benhamou MD
Professor of Hepatology, Université Denis Diderot Paris 7, Assistance Publique — Hôpitaux de Paris and Inserm U773, Service d'Hépatologie, Hôpital Beaujon, Clichy, France
Search for more papers by this authorAndres T. Blei MD
Professor of Medicine and Surgery, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA
Search for more papers by this authorJürg Reichen MD
Professor of Medicine, University of Bern; Chief of Hepatology, University Hospital, Bern, Switzerland
Search for more papers by this authorMario Rizzetto MD
Professor of Gastroenterology, University of Turin, Turin, Italy
Search for more papers by this authorFirst published: 18 June 2007
References
- Berggren S, Goldberg L (1940) The absorption of ethyl alcohol from the gastrointestinal tract as a diffusion process. Acta Physiol Scand 1, 246–270.
- Marshall AW, Kingstone D, Boss M, Morgan MY (1983) Ethanol elimination in males and females: relationship to menstrual cycle and body composition. Hepatology 3, 701–706.
- Caballeria J, Baraona E, Lieber CS (1987) The contribution of the stomach to ethanol oxidation in the rat. Life Sci 41, 1021–1027.
- Brown AS, Fiatarone JR, Wood P et al. (1995) The effect of gastritis on human gastric alcohol dehydrogenase activity and ethanol metabolism. Aliment Pharmacol Ther 9, 57–61.
- Lieber CS, DeCarli LM (1968) Ethanol oxidation by hepatic microsomes: adaptive increase after ethanol feeding. Science 162, 917–918.
- Umeno M, McBride OW, Yang CS et al. (1988) Human ethanol-inducible P450IIE1: complete gene sequence, promoter characterization, chromosome mapping, and cDNA-directed expression. Biochemistry 27 9006–9013.
- Boveris A, Oshino N, Chance B (1972) The cellular production of hydrogen peroxide. Biochem J 128, 617–630.
- Smith M (1986) Genetics of human alcohol and aldehyde dehydrogenases. Adv Hum Genet 15, 249–290.
- Goedde HW, Agarwal DP (1987) Polymorphism of aldehyde dehydrogenase and alcohol sensitivity. Enzyme 37, 29–44.
- Crabb DW, Edenberg HJ, Bosron WF, Li TK (1989) Genotypes for aldehyde dehydrogenase deficiency and alcohol sensitivity. The inactive ALDH2(2) allele is dominant. J Clin Invest 83, 314–316.
- Enomoto N, Takase S, Takada N, Takada A (1991) Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes. Hepatology 13, 1071–1075.
- Nuutinen H, Lindros KO, Salaspuro M (1983) Determinants of blood acetaldehyde level during ethanol oxidation in chronic alcoholics. Alcohol Clin Exp Res 7, 163–168.
- Korsten MA, Matsuzaki S, Feinman L, Lieber CS (1975) High blood acetaldehyde levels after ethanol administration. Difference between alcoholic and nonalcoholic subjects. N Engl J Med 292, 386–389.
- Lindros KO, Stowell A, Pikkarainen P, Salaspuro M (1980) Elevated blood acetaldehyde in alcoholics with accelerated ethanol elimination. Pharmacol Biochem Behav 13 (Suppl. 1), 119–124.
- Day CP, Yeaman SJ (1992) Physical evidence for the presence of two forms of phosphatidate phosphohydrolase in rat liver. Biochim Biophys Acta 1127, 87–94.
- Nanji AA, Tsukamoto H, French SW (1989) Relationship between fatty liver and subsequent development of necrosis, inflammation and fibrosis in experimental alcoholic liver disease. Exp Mol Pathol 51, 141–148.
- Elabbadi N, Day CP, Gamouh A et al. (2005) Relationship between the inhibition of phosphatidic acid phosphohydrolase-1 by oleate and oleoyl-CoA ester and its apparent translocation. Biochimie 87, 437–443.
- Aoyama T, Peters JM, Iritani N et al. (1998) Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem 273, 5678–5684.
- Galli A, Pinaire J, Fischer M et al. (2001) The transcriptional and DNA binding activity of peroxisome proliferator-activated receptor alpha is inhibited by ethanol metabolism. A novel mechanism for the development of ethanol-induced fatty liver. J Biol Chem 276, 68–75.
- Fischer M, You M, Matsumoto M, Crabb DW (2003) Peroxisome proliferator-activated receptor alpha (PPARalpha) agonist treatment reverses PPARalpha dysfunction and abnormalities in hepatic lipid metabolism in ethanol-fed mice. J Biol Chem 278, 27997–28004.
- Nanji AA, Dannenberg AJ, Jokelainen K, Bass NM (2004) Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation. J Pharmacol Exp Ther 310, 417–424.
- Nakajima T, Kamijo Y, Tanaka N et al. (2004) Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage [see comment]. Hepatology 40, 972–980.
- Sugimoto T, Yamashita S, Ishigami M et al. (2002) Decreased microsomal triglyceride transfer protein activity contributes to initiation of alcoholic liver steatosis in rats. J Hepatol 36, 157–162.
- Yin M, Wheeler MD, Kono H et al. (1999) Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117, 942–952.
- Ueki K, Kondo T, Tseng YH, Kahn CR (2004) Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Proc Natl Acad Sci USA 101, 10422–10427.
- Xu A, Wang Y, Keshaw H et al. (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112, 91–100.
- Villanueva JA, Halsted CH (2004) Hepatic transmethylation reactions in micropigs with alcoholic liver disease. Hepatology 39, 1303–1310.
- Kenyon SH, Nicolaou A, Gibbons WA (1998) The effect of ethanol and its metabolites upon methionine synthase activity in vitro. Alcohol 15, 305–309.
- Outinen PA, Sood SK, Pfeifer SI et al. (1999) Homocysteine-induced endoplasmic reticulum stress and growth arrest leads to specific changes in gene expression in human vascular endothelial cells. Blood 94, 959–967.
- You M, Fischer M, Deeg MA, Crabb DW (2002) Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP). J Biol Chem 277, 29342–29347.
- You M, Matsumoto M, Pacold CM et al. (2004) The role of AMP-activated protein kinase in the action of ethanol in the liver. Gastroenterology 127, 1798–1808.
- Ji C, Kaplowitz N (2003) Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 124, 1488–1499.
- Ji C, Deng Q, Kaplowitz N (2004) Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology 40, 442–451.
- Day CP, James OF (1998) Hepatic steatosis: innocent bystander or guilty party? Hepatology 27, 1463–1466.
- Sorensen TI, Orholm M, Bentsen KD et al. (1984) Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet ii, 41–44.
- Teli MR, Day CP, Burt AD et al. (1995) Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver [comment]. Lancet 346, 987–990.
- Yang SQ, Lin HZ, Lane MD et al. (1997) Obesity increases sensitivity to endotoxin liver injury: implications for the pathogenesis of steato-hepatitis. Proc Natl Acad Sci USA 94, 2557–2562.
- Letteron P, Fromenty B, Terris, B et al. (1996) Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice. J Hepatol 24, 200–208.
- Guebre-Xabier Xabier, Yang S, Lin HZ et al. (2000) Altered hepatic lymphocyte subpopulations in obesity-related murine fatty livers: potential mechanism for sensitization to liver damage. Hepatology 31, 633–640.
- Halliwell B (1994) Free radicals, antioxidants, and human disease: curiosity, cause, or consequence? [see comments] Lancet 344, 721–724.
- Parola M, Robino G (2001) Oxidative stress-related molecules and liver fibrosis. J Hepatol 35, 297–306.
- Ekstrom G, Ingelman-Sundberg M (1989) Rat liver microsomal NADPH-supported oxidase activity and lipid peroxidation dependent on ethanol-inducible cytochrome P-450 (P-450IIE1). Biochem Pharmacol 38, 1313–1319.
- Albano E, Tomasi A, Goria-Gatti, L, Dianzani MU (1988) Spin trapping of free radical species produced during the microsomal metabolism of ethanol. Chem-Biol Interact 65, 223–234.
- Slater TF, Sawyer BC, Strauli UD (1964) Changes in liver nucleotide concentrations in experimental liver injury. 2. Acute ethanol poisoning. Biochem J 93, 267–270.
- Paredes SR, Kozicki PA, Fukuda H et al. (1987) S-adenosyl-L-methionine: its effect on aminolevulinate dehydratase and glutathione in acute ethanol intoxication. Alcohol 4, 81–85.
- Hirano T, Kaplowitz N, Tsukamoto H et al. (1992) Hepatic mitochondrial glutathione depletion and progression of experimental alcoholic liver disease in rats. Hepatology 16, 1423–1427.
- Colell A, Garcia-Ruiz, C, Miranda M et al. (1998) Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor. Gastroenterology 115, 1541–1551.
- Dworkin B, Rosenthal WS, Jankowski RH et al. (1985) Low blood selenium levels in alcoholics with and without advanced liver disease. Correlations with clinical and nutritional status. Dig Dis Sci 30, 838–844.
- Thurnham DI, Davies JA, Crump BJ et al. (1986) The use of different lipids to express serum tocopherol: lipid ratios for the measurement of vitamin E status. Ann Clin Biochem 23, 514–520.
- Leo MA, Lieber CS (1982) Hepatic vitamin A depletion in alcoholic liver injury. N Engl J Med 307, 597–601.
- Bianchi GP, Fiorella PL, Bargossi AM et al. (1994) Reduced ubiquinone plasma levels in patients with liver cirrhosis and in chronic alcoholics. Liver 14, 138–140.
- Stewart SF, Prince M, Bassendine MF et al. (2002) A trial of antioxidant therapy alone or with corticosteroids in acute alcoholic hepatitis. J Hepatol 36 (Suppl. 1), 16.
- Nanji AA, Mendenhall CL, French SW (1989) Beef fat prevents alcoholic liver disease in the rat. Alcohol Clin Exp Res 13, 15–19.
- Nanji AA, French SW (1989) Dietary linoleic acid is required for development of experimentally induced alcoholic liver injury. Life Sci 44, 223–227.
- Nanji AA, Zhao S, Sadrzadeh SM et al. (1994) Markedly enhanced cytochrome P450 2E1 induction and lipid peroxidation is associated with severe liver injury in fish oil-ethanol-fed rats. Alcohol Clin Exp Res 18, 1280–1285.
- Tsukamoto H, Horne W, Kamimura S et al. (1995) Experimental liver cirrhosis induced by alcohol and iron. J Clin Invest 96, 620–630.
- Kessova IG, Ho YS, Thung S, Cederbaum AI (2003) Alcohol-induced liver injury in mice lacking Cu, Zn-superoxide dismutase. Hepatology 38, 1136–1145.
- Lu SC, Alvarez L, Huang ZZ et al. (2001) Methionine adenosyltrans-ferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci USA 98, 5560–5565.
- Lieber CS (2002) S-Adenosyl-L-methionine and alcoholic liver disease in animal models: implications for early intervention in human beings. Alcohol 27, 173–177.
- Sadrzadeh SM, Nanji AA, Price PL (1994) The oral iron chelator, 1,2-dimethyl-3-hydroxypyrid-4-one, reduces hepatic-free iron, lipid peroxidation and fat accumulation in chronically ethanol-fed rats. J Pharmacol Exp Ther 269, 632–636.
- Albano E, Clot P, Morimoto M et al. (1996) Role of cytochrome P4502E1-dependent formation of hydroxyethyl free radical in the development of liver damage in rats intragastrically fed with ethanol. Hepatology 23, 155–163.
- Morimoto M, Hagbjork AL, Nanji AA et al. (1993) Role of cytochrome P4502E1 in alcoholic liver disease pathogenesis. Alcohol 10, 459–464.
- Wheeler MD, Nakagami M, Bradford BU et al. (2001) Overexpres-sion of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biol Chem 276, 36664–36672.
- Kono H, Rusyn I, Yin M et al. (2000) NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 106, 867–872.
- Stevens VJ, Fantl WJ, Newman CB et al. (1981) Acetaldehyde adducts with hemoglobin. J Clin Invest 67, 361–369.
- Pastorino JG, Hoek JB (2000) Ethanol potentiates tumor necrosis factor-alpha cytotoxicity in hepatoma cells and primary rat hepatocytes by promoting induction of the mitochondrial permeability transition. Hepatology 31, 1141–1152.
- Lluis JM, Colell A, Garcia-Ruiz C et al. (2003) Acetaldehyde impairs mitochondrial glutathione transport in Hep G2 cells through endoplasmic reticulum stress. Gastroenterology 124, 708–724.
- Nolan JP (1989) Intestinal endotoxins as mediators of hepatic injury — an idea whose time has come again. Hepatology 10, 887–891.
- Fukui H, Brauner B, Bode JC, Bode C (1991) Plasma endotoxin concentrations in patients with alcoholic and non-alcoholic liver disease: reevaluation with an improved chromogenic assay. J Hepatol 12, 162–169.
- Nanji AA, Khettry U, Sadrzadeh SM, Yamanaka T (1993) Severity of liver injury in experimental alcoholic liver disease. Correlation with plasma endotoxin, prostaglandin E2, leukotriene B4, and thromboxane B2. Am J Pathol 142, 367–373.
- Schumann RR, Leong SR, Flaggs GW et al. (1990) Structure and function of lipopolysaccharide-binding protein. Science 249, 1429–1431.
- Poltorak A, He X, Smirnova I et al. (1998) Defective LPS signalling in C3H/HeJ and C57BL/10Sc Cr mice: mutations in Tlr4 gene. Science 282, 2085–2088.
- Pasare C, Medzhitov R (2003) Toll pathway-dependent blockade of CD4+CD25+ T cell-mediated suppression by dendritic cells [comment]. Science 299, 1033–1036.
- Tsukamoto H, Reidelberger RD, French SW, Largman C (1984) Long-term cannulation model for blood sampling and intragastric infusion in the rat. Am J Physiol 247, R595–599.
- Adachi Y, Moore LE, Bradford BU et al. (1995) Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108, 218–224.
- Uesugi T, Froh M, Arteel GE et al. (2001) Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34, 101–108.
- Jarvelainen HA, Orpana A, Perola M et al. (2001) Promoter polymorphism of the CD14 endotoxin receptor gene as a risk factor for alcoholic liver disease [see comment]. Hepatology 33, 1148–1153.
- Enomoto N, Ikejima K, Bradford B et al. (1998) Alcohol causes both tolerance and sensitization of rat Kupffer cells via mechanisms dependent on endotoxin. Gastroenterology 115, 443–451.
- Knolle PA, Gerken G (2000) Local control of the immune response in the liver. Immunol Rev 174, 21–34.
- McClain CJ, Cohen DA (1989) Increased tumor necrosis factor production by monocytes in alcoholic hepatitis. Hepatology 9, 349–351.
- Bird G, Sheron N, Goka AK et al. (1990) Increased plasma tumour necrosis factor in severe alcoholic hepatitis. Ann Intern Med 112, 917–920.
- Matsumaru K, Ji C, Kaplowitz N (2003) Mechanisms for sensitization to TNF-induced apoptosis by acute glutathione depletion in murine hepatocytes. Hepatology 37, 1425–1434.
- Natori S, Rust C, Stadheim LM et al. (2001) Hepatocyte apoptosis is a pathologic feature of human alcoholic hepatitis. J Hepatol 34, 248–253.
- Day CP (2001) Apoptosis in alcoholic hepatitis: a novel therapeutic target? [letter; comment]. J Hepatol 34, 330–333.
- Crispe IN, Mehal WZ (1996) Strange brew. T cells in the liver. Immunol Today 17, 522–525.
- Laso FJ, Madruga JI, Giron JA et al. (1997) Decreased natural killer cytotoxic activity in chronic alcoholism is associated with alcohol liver disease but not active ethanol consumption. Hepatology 25, 1096–1100.
- Minagawa M, Deng Q, Liu ZX et al. (2004) Activated natural killer T cells induce liver injury by Fas and tumor necrosis factor-alpha during alcohol consumption. Gastroenterology 126, 1387–1399.
- Mathurin P, Duchatelle V, Ramond MJ et al. (1996) Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology 110, 1847–1853.
- Zylberberg H, Fontaine H, Thepot V et al. (1999) Triggering of acute alcoholic hepatitis by alpha-interferon therapy. J Hepatol 30, 722–725.
- Chedid A, Mendenhall CL, Moritz TE et al. (1993) Cell-mediated hepatic injury in alcoholic liver disease. Veterans Affairs Cooperative Study Group 275. Gastroenterology 105, 254–266.
- Burt AD, Anthony RS, Hislop WS et al. (1982) Liver membrane antibodies in alcoholic liver disease: 1. prevalence and immunoglobulin class. Gut 23, 221–225.
- Trevisan A, Cavigli R, Meliconi R et al. (1983) Detection of immunoglobulins G and A on the cell membrane of hepatocytes from patients with alcoholic liver disease. J Clin Pathol 36, 530–534.
- Israel Y, Hurwitz E, Niemela O, Arnon R (1986) Monoclonal and polyclonal antibodies against acetaldehyde-containing epitopes in acetaldehyde-protein adducts. Proc Natl Acad Sci USA 83, 7923–7927.
- Nicholls RM, Fowles LF, Worrall S et al. (1994) Distribution and turnover of acetaldehyde-modified proteins in liver and blood of ethanol-fed rats. Alcohol Alcoholism 29, 149–157.
- Niemela O, Juvonen T, Parkkila S (1991) Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption. J Clin Invest 87, 1367–1374.
- Holstege A, Bedossa P, Poynard T et al. (1994) Acetaldehyde-modified epitopes in liver biopsy specimens of alcoholic and nonalcoholic patients: localization and association with progression of liver fibrosis. Hepatology 19, 367–374.
- Worrall S, De Jersey J, Shanley BC, Wilce PA (1990) Antibodies against acetaldehyde-modified epitopes: presence in alcoholic, nonalcoholic liver disease and control subjects. Alcohol Alcoholism 25, 509–517.
- Niemela O, Klajner F, Orrego H et al. (1987) Antibodies against acetaldehyde-modified protein epitopes in human alcoholics. Hepatology 7, 1210–1214.
- Albano E, Tomasi A, Persson JO et al. (1991) Role of ethanol-inducible cytochrome P450 (P450IIE1) in catalysing the free radical activation of aliphatic alcohols. Biochem Pharmacol 41, 1895–1902.
- Mottaran E, Stewart SF, Rolla R et al. (2002) Lipid peroxidation contributes to immune reactions associated with alcoholic liver disease. Free Radical Bio Med 32, 38–45.
- Clot P, Bellomo G, Tabone M et al. (1995) Detection of antibodies against proteins modified by hydroxyethyl free radicals in patients with alcoholic cirrhosis. Gastroenterology 108, 201–207.
- Rolla R, Vay D, Mottaran E et al. (2000) Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology 31, 878–884.
- Clot P, Albano E, Eliasson E et al. (1996) Cytochrome P4502E1 hydroxyethyl radical adducts as the major antigen in autoantibody formation among alcoholics. Gastroenterology 111, 206–216.
- Lytton SD, Helander A, Zhang-Gouillon ZQ et al. (1999) Autoantibodies against cytochromes P-4502E1 and P-4503A in alcoholics. Mol Pharmacol 55, 223–233.
- Vidali M, Stewart SF, Rolla R et al. (2003) Genetic and epigenetic factors in autoimmune reactions toward cytochrome P4502E1 in alcoholic liver disease. Hepatology 37, 410–419.
- Clot P, Parola M, Bellomo G et al. (1997) Plasma membrane hydroxyethyl radical adducts cause antibody-dependent cytotoxicity in rat hepatocytes exposed to alcohol [see comments]. Gastroenterology 113, 265–276.
- Stewart SF, Vidali M, Day CP et al. (2004) Oxidative stress as a trigger for cellular immune responses in patients with alcoholic liver disease. Hepatology 39, 197–203.
- Holt K, Bennett M, Chojkier M (1984) Acetaldehyde stimulates collagen and noncollagen protein production by human fibroblasts. Hepatology 4, 843–848.
- Ma X, Svegliati-Baroni, G, Poniachik J et al. (1997) Collagen synthesis by liver stellate cells is released from its normal feedback regulation by acetaldehyde-induced modification of the carboxyl-terminal propeptide of procollagen. Alcohol Clin Exp Res 21, 1204–1211.
- Nieto N, Friedman SL, Cederbaum AI (2002) Cytochrome P450 2E1-derived reactive oxygen species mediate paracrine stimulation of collagen I protein synthesis by hepatic stellate cells. J Biol Chem 277, 9853–9864.
- Canbay A, Higuchi H, Bronk SF et al. (2002) Fas enhances fibrogenesis in the bile duct ligated mouse: a link between apoptosis and fibrosis. Gastroenterology 123, 1323–1330.
- Canbay A, Taimr P, Torok N et al. (2003) Apoptotic body engulf-ment by a human stellate cell line is profibrogenic. Lab Invest 83, 655–663.
- Fadok VA, Bratton DL, Konowal A et al. (1998) Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF. J Clin Invest 101, 890–898.
- Nair S, Mason A, Eason J et al. (2002) Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis' Hepatology 36, 150–155
- [erratum appears in Hepatology (2002) 36, 774].
- Bellentani S, Saccoccio G, Costa, G et al. (1997) Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group [see comments]. Gut 41, 845–850.
- Lelbach WK (1975) Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Ann NY Acad Sci 252, 85–105.
- Becker U, Deis A, Sorensen TI et al. (1996) Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology 23, 1025–1029.
- Becker U, Gronbaek M, Johansen D, Sorensen TI (2002) Lower risk for alcohol-induced cirrhosis in wine drinkers [see comment]. Hepatology 35, 868–875.
- Nanji AA, French SW (1985) Relationship between pork consumption and cirrhosis. Lanceti, 681–683.
- Rotily M, Durbec JP, Berthezene P, Sarles H (1990) Diet and alcohol in liver cirrhosis: a case-control study. Eur J Clin Nutr 44, 595–603.
- Naveau S, Giraud V, Borotto, E et al. (1997) Excess weight risk factor for alcoholic liver disease. Hepatology 25, 108–111.
- Raynard B, Balian A, Fallik D et al. (2002) Risk factors of fibrosis in alcohol-induced liver disease. Hepatology 35, 635–638.
- Enomoto N, Takei Y, Kitamura T et al. (2002) Estriol enhances lipopolysaccharide-induced increases in nitric oxide production by Kupffer cells via mechanisms dependent on endotoxin. Alcohol Clin Exp Res 26 (8 Suppl.), 66S–69S.
- Hrubec Z, Omenn GS (1981) Evidence of genetic predisposition to alcoholic cirrhosis and psychosis: twin concordances for alcoholism and its biological end points by zygosity among male veterans. Alcohol Clin Exp Res 5, 207–215.
- Stinson FS, Grant BF, Dufour MC (2001) The critical dimension of ethnicity in liver cirrhosis mortality statistics. Alcohol Clin Exp Res 25, 1181–1187.
- Caetano R, Clark CL (1998) Trends in alcohol-related problems among whites, blacks, and Hispanics: 1984–1995. Alcohol Clin Exp Res 22, 534–538.
- Daly A, Day CP (2001) Candidate gene case-control association studies: advantages and pitfalls. Br J Clin Pharmacol 52, 489–499.
- Day CP, Leathart JB, Daly AK (2002) Genetic evidence that fatty liver is involved in the pathogenesis of advanced alcoholic liver disease. Hepatology 36 (Suppl. 1), 16.
- Chao YC, Young TH, Tang HS, Hsu CT (1997) Alcoholism and alcoholic organ damage and genetic polymorphisms of alcohol metabolizing enzymes in Chinese patients. Hepatology 25, 112–117.
- Chao YC, Wang LS, Hsieh TY et al. (2000) Chinese alcoholic patients with esophageal cancer are genetically different from alcoholics with acute pancreatitis and liver cirrhosis. Am J Gastroenterol 95, 2958–2964.
- Tanaka F, Shiratori Y, Yokosuka O et al. (1996) High incidence of ADH2*1/ALDH2*1 genes among Japanese alcohol dependents and patients with alcoholic liver disease. Hepatology 23, 234–239.
- Osier M, Pakstis AJ, Kidd Jr et al. (1999) Linkage disequilibrium at the ADH2 and ADH3 loci and risk of alcoholism. Am J Hum Genet 64, 1147–1157.
- Borras E, Coutelle C, Rosell A et al. (2000) Genetic polymorphism of alcohol dehydrogenase in Europeans: the ADH2*2 allele decreases the risk for alcoholism and is associated with ADH3*1. Hepatology 31, 984–989.
- Grove J, Brown AS, Daly AK et al. (1998) The Rsa I polymorphism of CYP2E1 and susceptibility to alcoholic liver disease in Caucasians: effect on age of presentation and dependence on alcohol dehydrogenase genotype. Pharmacogenetics 8, 335–342.
- Degoul F, Sutton A, Mansouri A et al. (2001) Homozygosity for alanine in the mitochondrial targeting sequence of superoxide dis-mutase and risk for severe alcoholic liver disease. Gastroenterology 120, 1468–1474.
- Stewart SF, Leathart JB, Chen Y et al. (2002) Valine-alanine manganese superoxide dismutase polymorphism is not associated with alcohol-induced oxidative stress or liver fibrosis. Hepatology 36, 1355–1360.
- Baldini M, Lohman IC, Halonen M et al. (1999) A polymorphism* in the 5'flanking region of the CD14 gene is associated with circulating soluble CD14 levels and with total serum immunoglobulin E. Am J Respir Cell Mol Biol 20, 976–983.
- Leathart JB, Day CP, Daly AK (2001) No association between functional SNPs in the endotoxin receptors CD14 and TLR4 and alcoholic liver disease (ALD): is endotoxin important in the pathogenesis of ALD in humans' Hepatology 34, 459A.
- Arbour NC, Lorenz E, Schutte BC et al. (2000) TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 25, 187–191.
- Grove J, Daly AK, Bassendine MF, Day CP (1997) Association of a tumor necrosis factor promoter polymorphism with susceptibility to alcoholic steatohepatitis. Hepatology 26, 143–146.
- Grove J, Daly AK, Bassendine MF et al. (2000) Interleukin 10 promoter region polymorphisms and susceptibility to advanced alcoholic liver disease [see comment]. Gut 46, 540–545.
- Waterhouse P, Marengere LE, Mittrucker HW, Mak TW (1996) CTLA-4, a negative regulator of T-lymphocyte activation. Immunol Rev 153, 183–207.
- Valenti L, De Feo T, Fracanzani AL et al. (2004) Cytotoxic T-lymphocyte antigen-4 A49G polymorphism is associated with susceptibility to and severity of alcoholic liver disease in Italian patients. Alcohol Alcoholism 39, 276–280.
