Nutrition and Alcoholic Liver Disease

Malnutrition is a common finding in chronic alcoholics, and protein calorie malnutrition (PCM) is universal and predictive of survival in patients with established alcoholic liver disease (ALD). These patients also demonstrate frequent deficiencies of folate, thiamine, pyridoxine, and vitamin A, which enhance the likelihood of anemia, altered cognitive states, and night blindness. The etiologies of malnutrition in ALD patients are multiple and interactive and include anorexia with inadequate dietary intake, abnormal digestion of macronutrients and absorption of several micronutrients, increased skeletal and visceral protein catabolism, and abnormal interactions of ethanol and lipid metabolism. Numerous, and mostly inadequately controlled, studies have evaluated the potential efficacies of oral, enteral, and parenteral nutrition approaches to treatment of ALD, with mixed results on liver function, clinical improvements, and short- or long-term survival. Targeted metabolic treatments include supplementation with S-adenosylmethionine (SAM) or phosphatidylcholine derivatives, each with promising experimental bases but inconclusive clinical trials.

Nutrition - alcoholism - liver - S-adenosylmethionine - phosphatidylcholine

REFERENCES

• 1 Mendenhall C L, Anderson S, Weesner R E, Goldberg S J, Crolic K A. Protein-calorie malnutrition associated with alcoholic hepatitis. Veterans Administration Cooperative Study Group on Alcoholic Hepatitis.  Am J Med. 1984;  76 211-222
• 2 Pirola R C, Lieber C S. The energy cost of the metabolism of drugs, including ethanol.  Pharmacology. 1972;  7 185-196
• 3 Suter P M, Schutz Y, Jequier E. The effect of ethanol on fat storage in healthy subjects.  N Engl J Med. 1992;  326 983-987
• 4 Sonko B J, Prentice A M, Murgatroyd P R et al.. Effect of alcohol on postmeal fat storage.  Am J Clin Nutr. 1994;  59 619-625
• 5 Rubin E, Lieber C S. Alcohol-induced hepatic injury in nonalcoholic volunteers.  N Engl J Med. 1968;  278 869-876
• 6 Lieber C S, Jones D P, Decarli L M. Effects of prolonged ethanol intake: production of fatty liver despite adequate diets.  J Clin Invest. 1965;  44 1009-1021
• 7 Mendenhall C L, Tosch T, Weesner R E et al.. VA cooperative study on alcoholic hepatitis. II: Prognostic significance of protein-calorie malnutrition.  Am J Clin Nutr. 1986;  43 213-218
• 8 Patek Jr A J, Toth I G, Saunders M G, Castro G A, Engel J J. Alcohol and dietary factors in cirrhosis. An epidemiological study of 304 alcoholic patients.  Arch Intern Med. 1975;  135 1053-1057
• 9 Richardson R A, Davidson H I, Hinds A et al.. Influence of the metabolic sequelae of liver cirrhosis on nutritional intake.  Am J Clin Nutr. 1999;  69 331-337
• 10 Mendenhall C L, Moritz T E, Roselle G A et al.. A study of oral nutritional support with oxandrolone in malnourished patients with alcoholic hepatitis: results of a Department of Veterans Affairs cooperative study.  Hepatology. 1993;  17 564-576
• 11 Felver M E, Mezey E, McGuire M et al.. Plasma tumor necrosis factor alpha predicts decreased long-term survival in severe alcoholic hepatitis.  Alcohol Clin Exp Res. 1990;  14 255-259
• 12 Khoruts A, Stahnke L, McClain C J, Logan G, Allen J I. Circulating tumor necrosis factor, interleukin-1 and interleukin-6 concentrations in chronic alcoholic patients.  Hepatology. 1991;  13 267-276
• 13 McCullough A J, Bugianesi E, Marchesini G, Kalhan S C. Gender-dependent alterations in serum leptin in alcoholic cirrhosis.  Gastroenterology. 1998;  115 947-953
• 14 Potter J J, Womack L, Mezey E, Anania F A. Transdifferentiation of rat hepatic stellate cells results in leptin expression.  Biochem Biophys Res Commun. 1998;  244 178-182
• 15 Muller M J, Lautz H U, Plogmann B et al.. Energy expenditure and substrate oxidation in patients with cirrhosis: the impact of cause, clinical staging and nutritional state.  Hepatology. 1992;  15 782-794
• 16 Selberg O, Bottcher J, Tusch G et al.. Identification of high- and low-risk patients before liver transplantation: a prospective cohort study of nutritional and metabolic parameters in 150 patients.  Hepatology. 1997;  25 652-657
• 17 Schneeweiss B, Graninger W, Ferenci P et al.. Energy metabolism in patients with acute and chronic liver disease.  Hepatology. 1990;  11 387-393
• 18 Linscheer W G, Patterson J F, Moore E W et al.. Medium and long chain fat absorption in patients with cirrhosis.  J Clin Invest. 1966;  45 1317-1325
• 19 Roggin G M, Iber F L, Linscheer W G. Intraluminal fat digestion in the chronic alcoholic.  Gut. 1972;  13 107-111
• 20 Soberon S, Pauley M P, Duplantier R, Fan A, Halsted C H. Metabolic effects of enteral formula feeding in alcoholic hepatitis.  Hepatology. 1987;  7 1204-1209
• 21 Leevy C M, Baker H, Tenhove W, Frank O, Cherrick G R. B-complex vitamins in liver disease of the alcoholic.  Am J Clin Nutr. 1965;  16 339-346
• 22 Herbert V, Zalusky R, Davidson C S. Correlation of folate deficiency with alcoholism and associated macrocytosis, anemia, and liver disease.  Ann Intern Med. 1963;  58 977-988
• 23 Savage D, Lindenbaum J. Anemia in alcoholics.  Medicine (Baltimore). 1986;  65 322-338
• 24 Eichner E R, Hillman R S. The evolution of anemia in alcoholic patients.  Am J Med. 1971;  50 218-232
• 25 Leo M A, Lieber C S. Hepatic vitamin A depletion in alcoholic liver injury.  N Engl J Med. 1982;  307 597-601
• 26 Hermos J A, Adams W H, Lin Y K, Sullivan L W, Trier J S. Mucosa of the small intestine in folate deficient alcoholics.  Ann Intern Med. 1972;  76 957-965
• 27 Cravo M. Hyperhomocysteinemia in chronic alcoholism: correlation with folate, vitamin B-12, and vitamin B-6 status.  Am J Clin Nutr. 1996;  63 220-224
• 28 Herbert V. Experimental nutritional folate deficiency in man.  Trans Assoc Am Physicians. 1962;  75 307-320
• 29 Halsted C H, Robles E A, Mezey E. Decreased jejunal uptake of labeled folic acid (3 H-PGA) in alcoholic patients: roles of alcohol and nutrition.  N Engl J Med. 1971;  285 701-706
• 30 Halsted C H, Robles E A, Mezey E. Intestinal malabsorption in folate-deficient alcoholics.  Gastroenterology. 1973;  64 526-532
• 31 Romero J J, Tamura T, Halsted C H. Intestinal absorption of [³H]folic acid in the chronic alcoholic monkey.  Gastroenterology. 1981;  80 99-102
• 32 Naughton C A, Chandler C J, Duplantier R B, Halsted C H. Folate absorption in alcoholic pigs: in vitro hydrolysis and transport at the intestinal brush border membrane.  Am J Clin Nutr. 1989;  50 1436-1441
• 33 Reisenauer A M, Buffington C A, Villanueva J A, Halsted C H. Folate absorption in alcoholic pigs: in vivo intestinal perfusion studies.  Am J Clin Nutr. 1989;  50 1429-1435
• 34 Villanueva J A, Devlin A M, Halsted C H. Reduced folate carrier: tissue distribution and effects of chronic ethanol intake in the micropig.  Alcohol Clin Exp Res. 2001;  25 415-420
• 35 Steinberg S E, Campbell C L, Hillman R S. Kinetics of the normal folate enterohepatic cycle.  J Clin Invest. 1979;  64 83-88
• 36 Tamura T, Romero J J, Watson J E, Gong E J, Halsted C H. Hepatic folate metabolism in the chronic alcoholic monkey.  J Lab Clin Med. 1981;  97 654-661
• 37 McMartin K E, Collins T D. Relationship of alcohol metabolism to folate deficiency produced by ethanol in the rat.  Pharmacol Biochem Behav. 1983;  18(suppl 1) 257-262
• 38 McMartin K E, Collins T D, Shiao C Q, Vidrine L, Redetzki H M. Study of dose-dependence and urinary folate excretion produced by ethanol in humans and rats.  Alcohol Clin Exp Res. 1986;  10 419-424
• 39 Russell R M, Rosenberg I H, Wilson P D et al.. Increased urinary excretion and prolonged turnover time of folic acid during ethanol ingestion.  Am J Clin Nutr. 1983;  38 64-70
• 40 Tamura T, Halsted C H. Folate turnover in chronically alcoholic monkeys.  J Lab Clin Med. 1983;  101 623-628
• 41 Sikka P K, McMartin K E. Determination of folate transport pathways in cultured rat proximal tubule cells.  Chem Biol Interact. 1998;  114 15-31
• 42 Ross D M, McMartin K E. Effect of ethanol on folate binding by isolated rat renal brush border membranes.  Alcohol. 1996;  13 449-454
• 43 Reuler J B, Girard D E, Cooney T G. Current concepts. Wernicke’s encephalopathy.  N Engl J Med. 1985;  312 1035-1039
• 44 Harper C. The neuropathology of alcohol-specific brain damage, or does alcohol damage the brain?.  J Neuropathol Exp Neurol. 1998;  57 101-110
• 45 Harper C G, Sheedy D L, Lara A I et al.. Prevalence of Wernicke-Korsakoff syndrome in Australia: has thiamine fortification made a difference?.  Med J Aust. 1998;  168 542-545
• 46 Lavoie J, Butterworth R F. Reduced activities of thiamine-dependent enzymes in brains of alcoholics in the absence of Wernicke’s encephalopathy.  Alcohol Clin Exp Res. 1995;  19 1073-1077
• 47 Blass J P, Gibson G E. Abnormality of a thiamine-requiring enzyme in patients with Wernicke-Korsakoff syndrome.  N Engl J Med. 1977;  297 1367-1370
• 48 Martin P R, McCool B A, Singleton C K. Molecular genetics of transketolase in the pathogenesis of the Wernicke-Korsakoff syndrome.  Metab Brain Dis. 1995;  10 45-55
• 49 Martin P R, Pekovich S R, McCool B A, Whetsell W O, Singleton C K. Thiamine utilization in the pathogenesis of alcohol-induced brain damage.  Alcohol Alcohol Suppl. 1994;  2 273-279
• 50 Mills P R, Shenkin A, Anthony R S et al.. Assessment of nutritional status and in vivo immune responses in alcoholic liver disease.  Am J Clin Nutr. 1983;  38 849-859
• 51 Thomson A D, Baker H, Leevy C M. Patterns of 35S-thiamine hydrochloride absorption in the malnourished alcoholic patient.  J Lab Clin Med. 1970;  76 34-45
• 52 Hoyumpa Jr A M, Nichols S G, Wilson F A, Schenker S. Effect of ethanol on intestinal (Na, K) ATPase and intestinal thiamine transport in rats.  J Lab Clin Med. 1977;  90 1086-1095
• 53 Mitchell D, Wagner C, Stone W J, Wilkinson G R, Schenker S. Abnormal regulation of plasma pyridoxal 5′-phosphate in patients with liver disease.  Gastroenterology. 1976;  71 1043-1049
• 54 Gloria L, Cravo M, Camilo M E et al.. Nutritional deficiencies in chronic alcoholics: relation to dietary intake and alcohol consumption.  Am J Gastroenterol. 1997;  92 485-489
• 55 Lumeng L. The role of acetaldehyde in mediating the deleterious effect of ethanol on pyridoxal 5′-phosphate metabolism.  J Clin Invest. 1978;  62 286-293
• 56 Yamada M, Blaner W S, Soprano D R et al.. Biochemical characteristics of isolated rat liver stellate cells.  Hepatology. 1987;  7 1224-1229
• 57 Moriwaki H, Blaner W S, Piantedosi R, Goodman D S. Effects of dietary retinoid and triglyceride on the lipid composition of rat liver stellate cells and stellate cell lipid droplets.  J Lipid Res. 1988;  29 1523-1534
• 58 Lakshman M R, Sundaresan P R, Chambers L L, Shoff P K. Cellular retinyl esters and retinol among parenchymal and stellate cells in normal rat liver.  Lipids. 1988;  23 144-147
• 59 Troen G, Nilsson A, Norum K R, Blomhoff R. Characterization of liver stellate cell retinyl ester storage.  Biochem J. 1994;  300 793-798
• 60 Liu C, Russell R M, Seitz H K, Wang X D. Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P4502E1.  Gastroenterology. 2001;  120 179-189
• 61 Leo M A, Lieber C S. Alcohol, vitamin A, and β-carotene: adverse interactions, including hepatotoxicity and carcinogenicity.  Am J Clin Nutr. 1999;  69 1071-1085
• 62 Hautekeete M L, Dodeman I, Azais-Braesco V et al.. Hepatic stellate cells and liver retinoid content in alcoholic liver disease in humans.  Alcohol Clin Exp Res. 1998;  22 494-500
• 63 Hellemans K, Rombouts K, Quartier E et al.. PPARbeta regulates vitamin A metabolism-related gene expression in hepatic stellate cells undergoing activation.  J Lipid Res. 2003;  44 280-295
• 64 Hellemans K, Verbuyst P, Quartier E et al.. Differential modulation of rat hepatic stellate phenotype by natural and synthetic retinoids.  Hepatology. 2004;  39 97-108
• 65 Chung J, Chavez P R, Russell R M, Wang X D. Retinoic acid inhibits hepatic Jun N-terminal kinase-dependent signaling pathway in ethanol-fed rats.  Oncogene. 2002;  21 1539-1547
• 66 Lelbach W K. Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse.  Ann N Y Acad Sci. 1975;  252 85-105
• 67 Lieber C S, DeCarli L M. An experimental model of alcohol feeding and liver injury in the baboon.  J Med Primatol. 1974;  3 153-163
• 68 Finkelstein J D. Pathways and regulation of homocysteine metabolism in mammals.  Semin Thromb Hemost. 2000;  26 219-225
• 69 Mato J M, Corrales F J, Pajares M A. S-adenosylmethionine and the liver. In: Arias IM, Fausto N, Jakoby WB, Schachter DA, Shafritz DA The Liver: Biology and Pathobiology, 3rd ed. New York; Raven Press 1994: 461-470
• 70 Lu S C. Methionine adenosyltransferase and liver disease: it’s all about SAM.  Gastroenterology. 1998;  114 403-407
• 71 Clarke S, Banfield K. S-Adenosylmethionine-dependent methyltransferases. In: Carmel R, Jacobsen DW Homocysteine in Health and Disease. Cambridge; Cambridge University Press 2001: 63-78
• 72 Kloor D, Fuchs S, Petroktistis F et al.. Effects of ions on adenosine binding and enzyme activity of purified S-adenosylhomocysteine hydrolase from bovine kidney.  Biochem Pharmacol. 1998;  56 1493-1496
• 73 Yi P, Melnyk S, Pogribna M et al.. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation.  J Biol Chem. 2000;  275 29318-29323
• 74 Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice.  Gastroenterology. 2003;  124 1488-1499
• 75 Finkelstein J D, Kyle W E, Martin J L, Pick A M. Activation of cystathionine synthase by adenosylmethionine and adenosylethionine.  Biochem Biophys Res Commun. 1975;  66 81-87
• 76 Cabrero C, Duce A M, Ortiz P, Alemany S, Mato J M. Specific loss of the high-molecular-weight form of S-adenosyl-L-methionine synthetase in human liver cirrhosis.  Hepatology. 1988;  8 1530-1534
• 77 Avila M A, Berasain C, Torres L et al.. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma.  J Hepatol. 2000;  33 907-914
• 78 Marchesini G, Bugianesi E, Bianchi G et al.. Defective methionine metabolism in cirrhosis: relation to severity of liver disease.  Hepatology. 1992;  16 149-155
• 79 Russmann S, Junker E, Lauterburg B H. Remethylation and transsulfuration of methionine in cirrhosis: studies with L-[H3-methyl-1-C]methionine.  Hepatology. 2002;  36 1190-1196
• 80 Look M P, Riezler R, Reichel C et al.. Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase?.  Scand J Gastroenterol. 2000;  35 866-872
• 81 Lee T D, Sadda M R, Mendler M H et al.. Abnormal hepatic methionine and glutathione metabolism in patients with alcoholic hepatitis.  Alcohol Clin Exp Res. 2004;  28 173-181
• 82 Barak A J, Beckenhauer H C, Tuma D J, Badakhsh S. Effects of prolonged ethanol feeding on methionine metabolism in rat liver.  Biochem Cell Biol. 1987;  65 230-233
• 83 Finkelstein J D, Kyle W E, Harris B J. Methionine metabolism in mammals: regulatory effects of S- adenosylhomocysteine.  Arch Biochem Biophys. 1974;  165 774-779
• 84 Trimble K C, Molloy A M, Scott J M, Weir D G. The effect of ethanol on one-carbon metabolism: increased methionine catabolism and lipotrope methyl-group wastage.  Hepatology. 1993;  18 984-989
• 85 Lu S C, Huang Z Z, Yang H et al.. Changes in methionine adenosyltransferase and S-adenosylmethionine homeostasis in alcoholic rat liver.  Am J Physiol Gastrointest Liver Physiol. 2000;  279 G178-G185
• 86 Pajares M A, Duran C, Corrales F, Pliego M M, Mato J M. Modulation of rat liver S-adenosylmethionine synthetase activity by glutathione.  J Biol Chem. 1992;  267 17598-17605
• 87 Avila M A, Mingorance J, Martinez-Chantar M L et al.. Regulation of rat liver S-adenosylmethionine synthetase during septic shock: role of nitric oxide.  Hepatology. 1997;  25 391-396
• 88 Lu S C, Alvarez L, Huang Z Z et al.. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation.  Proc Natl Acad Sci USA. 2001;  98 5560-5565
• 89 Mato J M, Corrales F J, Lu S C, Avila M A. S-Adenosylmethionine: a control switch that regulates liver function.  FASEB J. 2002;  16 15-26
• 90 Halsted C H, Villanueva J, Chandler C J et al.. Centrilobular distribution of acetaldehyde and collagen in the ethanol-fed micropig.  Hepatology. 1993;  18 954-960
• 91 Niemela O, Parkkila S, Yla-Herttuala S et al.. Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease.  Hepatology. 1995;  22 1208-1214
• 92 Halsted C H, Villanueva J, Chandler C J et al.. Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation.  Hepatology. 1996;  23 497-505
• 93 Halsted C H, Villanueva J A, Devlin A M et al.. Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig.  Proc Natl Acad Sci USA. 2002;  99 10072-10077
• 94 Villanueva J A, Halsted C H. Hepatic transmethylation reactions in micropigs with alcoholic liver disease.  Hepatology. 2004;  39 1303-1310
• 95 Wan Y J, An D, Cai Y et al.. Hepatocyte-specific mutation establishes retinoid X receptor alpha as a heterodimeric integrator of multiple physiological processes in the liver.  Mol Cell Biol. 2000;  20 4436-4444
• 96 Stickel F, Hoehn B, Schuppan D, Seitz H K. Review article: Nutritional therapy in alcoholic liver disease.  Aliment Pharmacol Ther. 2003;  18 357-373
• 97 Shanbhogue R L, Bistrian B R, Jenkins R L et al.. Resting energy expenditure in patients with end-stage liver disease and in normal population JPEN.  J Parenter Enteral Nutr. 1987;  11 305-308
• 98 Nompleggi D J, Bonkovsky H L. Nutritional supplementation in chronic liver disease: an analytical review.  Hepatology. 1994;  19 518-533
• 99 Schenker S, Halff G A. Nutritional therapy in alcoholic liver disease.  Semin Liver Dis. 1993;  13 196-209
• 100 Halsted C H. Role of nutrition in the treatment of alcoholic liver disease. In: Arroyo V, Bosch J, Bruguera M, Rodes J, Tapias JMS Treatment of Liver Diseases. Barcelona; Massan 1999: 221-231
• 101 Bunout D, Aicardi V, Hirsch S et al.. Nutritional support in hospitalized patients with alcoholic liver disease.  Eur J Clin Nutr. 1989;  43 615-621
• 102 Nielsen K, Kondrup J, Martinsen L et al.. Long-term oral refeeding of patients with cirrhosis of the liver.  Br J Nutr. 1995;  74 557-567
• 103 Campillo B, Bories P N, Pornin B, Devanlay M. Influence of liver failure, ascites, and energy expenditure on the response to oral nutrition in alcoholic liver cirrhosis.  Nutrition. 1997;  13 613-621
• 104 Kearns P J, Young H, Garcia G et al.. Accelerated improvement of alcoholic liver disease with enteral nutrition.  Gastroenterology. 1992;  102 200-205
• 105 Cabre E, Rodriguez-Iglesias P, Caballeria J et al.. Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial.  Hepatology. 2000;  32 36-42
• 106 Bonkovsky H L, Fiellin D A, Smith G S et al.. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. I. Short-term effects on liver function.  Am J Gastroenterol. 1991;  86 1200-1208
• 107 Bonkovsky H L, Singh R H, Jafri I H et al.. A randomized, controlled trial of treatment of alcoholic hepatitis with parenteral nutrition and oxandrolone. II. Short-term effects on nitrogen metabolism, metabolic balance, and nutrition.  Am J Gastroenterol. 1991;  86 1209-1218
• 108 Plauth M, Merli M, Kondrup J. Management of hepatic encephalopathy.  N Engl J Med. 1997;  337 1921-1922
• 109 Kajiwara K, Okuno M, Kobayashi T et al.. Oral supplementation with branched-chain amino acids improves survival rate of rats with carbon tetrachloride-induced liver cirrhosis.  Dig Dis Sci. 1998;  43 1572-1579
• 110 Marchesini G, Bianchi G, Merli M et al.. Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial.  Gastroenterology. 2003;  124 1792-1801
• 111 Lieber C S, Casini A, DeCarli L M et al.. S-adenosyl-L-methionine attenuates alcohol-induced liver injury in the baboon.  Hepatology. 1990;  11 165-172
• 112 Garcia-Ruiz C, Morales A, Colell A et al.. Feeding S-adenosyl-L-methionine attenuates both ethanol-induced depletion of mitochondrial glutathione and mitochondrial dysfunction in periportal and perivenous rat hepatocytes.  Hepatology. 1995;  21 207-214
• 113 Colell A, García-Ruiz C, Morales A et al.. Transport of reduced glutathione in hepatic mitochondria and mitoplasts from ethanol-treated rats: effect of membrane physical properties and S-adenosyl-L-methionine.  Hepatology. 1997;  26 699-708
• 114 Song Z, Zhou Z, Chen T et al.. S-adenosylmethionine (SAMe) protects against acute alcohol induced hepatotoxicity in mice.  J Nutr Biochem. 2003;  14 591-597
• 115 Hevia H, Varela-Rey M, Corrales F J et al.. 5′-methylthioadenosine modulates the inflammatory response to endotoxin in mice and in rat hepatocytes.  Hepatology. 2004;  39 1088-1098
• 116 Chawla R K, Watson W H, Eastin C E et al.. S-adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide- induced hepatic injury.  Am J Physiol. 1998;  275 G125-G129
• 117 Colell A, Garcia-Ruiz C, Miranda M et al.. Selective glutathione depletion of mitochondria by ethanol sensitizes hepatocytes to tumor necrosis factor.  Gastroenterology. 1998;  115 1541-1551
• 118 Watson W H, Zhao Y, Chawla R K. S-adenosylmethionine attenuates the lipopolysaccharide-induced expression of the gene for tumour necrosis factor alpha.  Biochem J. 1999;  342 21-25
• 119 Majano P L, Garcia-Monzon C, Garcia-Trevijano E R et al.. S-Adenosylmethionine modulates inducible nitric oxide synthase gene expression in rat liver and isolated hepatocytes.  J Hepatol. 2001;  35 692-699
• 120 Song Z, Barve S, Chen T et al.. S-adenosylmethionine (AdoMet) modulates endotoxin stimulated interleukin-10 production in monocytes.  Am J Physiol Gastrointest Liver Physiol. 2003;  284 G949-G955
• 121 Werstuck G H, Lentz S R, Dayal S et al.. Homocysteine-induced endoplasmic reticulum stress causes dysregulation of the cholesterol and triglyceride biosynthetic pathways.  J Clin Invest. 2001;  107 1263-1273
• 122 Loguercio C, Nardi G, Argenzio F et al.. Effect of S-adenosyl-L-methionine administration on red blood cell cysteine and glutathione levels in alcoholic patients with and without liver disease.  Alcohol Alcohol. 1994;  29 597-604
• 123 Vendemiale G, Altomare E, Trizio T et al.. Effects of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease.  Scand J Gastroenterol. 1989;  24 407-415
• 124 Mato J M, Caballeria J, Camara J et al.. Treatment of alcoholic liver disease with S-adenosylmethionine. In: Arroyo V, Bosch J, Bruguera M, Rodes J, Sanchez-Tapias J Treatment of Liver Diseases. Barcelona; Masson 1999: 233-242
• 125 French S W, Ihrig T J, Morin R J. Lipid composition of RBC ghosts, liver mitochondria and microsomes of ethanol-fed rats.  Q J Stud Alcohol. 1970;  31 801-809
• 126 Arai M, Gordon E R, Lieber C S. Decreased cytochrome oxidase activity in hepatic mitochondria after chronic ethanol consumption and the possible role of decreased cytochrome aa3 content and changes in phospholipids.  Biochim Biophys Acta. 1984;  797 320-327
• 127 Duce A M, Ortíz P, Cabrero C, Mato J M. S-adenosyl-L-methionine synthetase and phospholipid methyltransferase are inhibited in human cirrhosis.  Hepatology. 1988;  8 65-68
• 128 Lieber C S, Robins S J, Leo M A. Hepatic phosphatidylethanolamine methyltransferase activity is decreased by ethanol and increased by phosphatidylcholine.  Alcohol Clin Exp Res. 1994;  18 592-595
• 129 Lieber C S, DeCarli L M, Mak K M, Kim C I, Leo M A. Attenuation of alcohol-induced hepatic fibrosis by polyunsaturated lecithin.  Hepatology. 1990;  12 1390-1398
• 130 Lieber C S, Robins S J, Li J et al.. Phosphatidylcholine protects against fibrosis and cirrhosis in the baboon.  Gastroenterology. 1994;  106 152-159
• 131 Lieber C S, Leo M A, Mak K M, DeCarli L M, Sato S. Choline fails to prevent liver fibrosis in ethanol-fed baboons but causes toxicity.  Hepatology. 1985;  5 561-572
• 132 Aleynik S I, Lieber C S. Polyenylphosphatidylcholine corrects the alcohol-induced hepatic oxidative stress by restoring s-adenosylmethionine.  Alcohol Alcohol. 2003;  38 208-212
• 133 Aleynik M K, Lieber C S. Dilinoleoylphosphatidylcholine decreases ethanol-induced cytochrome P4502E1.  Biochem Biophys Res Commun. 2001;  288 1047-1051
• 134 Aleynik M K, Leo M A, Aleynik S I, Lieber C S. Polyenylphosphatidylcholine opposes the increase of cytochrome P-4502E1 by ethanol and corrects its iron-induced decrease.  Alcohol Clin Exp Res. 1999;  23 96-100
• 135 Cao Q, Mak K M, Lieber C S. Dilinoleoylphosphatidylcholine decreases acetaldehyde-induced TNF-alpha generation in Kupffer cells of ethanol-fed rats.  Biochem Biophys Res Commun. 2002;  299 459-464
• 136 Mak K M, Wen K, Ren C, Lieber C S. Dilinoleoylphosphatidylcholine reproduces the antiapoptotic actions of polyenylphosphatidylcholine against ethanol-induced hepatocyte apoptosis.  Alcohol Clin Exp Res. 2003;  27 997-1005
• 137 Lieber C S, Weiss D G, Groszmann R, Paronetto F, Schenker S. II. Veterans Affairs Cooperative Study of Polyenylphosphatidylcholine in Alcoholic Liver Disease.  Alcohol Clin Exp Res. 2003;  27 1765-1772