Diagnosis and Therapy of Alcoholic Liver Disease

Alcoholic liver disease (ALD) presents considerable challenges to clinicians. Screening for alcohol abuse and alcoholism should be routine and repeated annually with close attention to signs and symptoms of liver disease. In patients with evidence of liver dysfunction or injury, consideration should be given to performance of liver biopsy for diagnosis and prognosis and prior to initiation of medication with the potential for significant side effects. Therapy depends on the spectrum of pathological liver injury: alcoholic fatty liver, alcoholic hepatitis, and cirrhosis. Abstention is the foundation of therapy for an alcohol problem. Alcoholic fatty liver should improve with abstention, but the similarity to the pathogenesis of nonalcoholic fatty liver and potential for progressive injury merits consideration of lipotropic agents. The continuing mortality, poor acceptance of corticosteroids, and identification of tumor necrosis factor-alpha (TNF-α) as an integral component has led to studies of pentoxifylline and, recently, anti-TNF antibody to neutralize cytokines in the therapy of severe alcoholic hepatitis. Antioxidant therapy of alcoholic cirrhosis has significant promise but will require large clinical trials.

KEYWORDS

Liver disease - alcoholic - corticosteroids - tumor necrosis factor-alpha - antibodies - monoclonal

REFERENCES

• 1 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
• 2 McCullough A J, O'Connor J F. Alcoholic liver disease: proposed recommendations for the American College of Gastroenterology.  Am J Gastroenterol. 1998;  93 2022-2036
• 3 Becker U, Deis A, Sorensen T I et al.. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study.  Hepatology. 1996;  23 1025-1029
• 4 Cleary P D, Miller M, Bush B T et al.. Prevalence and recognition of alcohol abuse in a primary care population.  Am J Med. 1988;  85 466-471
• 5 Friedmann P D, McCullough D, Chin M H, Saitz R. Screening and intervention for alcohol problems. A national survey of primary care physicians and psychiatrists.  J Gen Intern Med. 2000;  15 84-91
• 6 U.S. Preventive Services Task Force .Guide to Clinical Preventive Services, 2nd ed. Baltimore; Williams and Wilkins 1986
• 7 Hoeksema H L, de Bock G H. The value of laboratory tests for the screening and recognition of alcohol abuse in primary care patients.  J Fam Pract. 1993;  37 268-276
• 8 Skinner H A, Holt S, Schuller R et al.. Identification of alcohol abuse using laboratory tests and a history of trauma.  Ann Intern Med. 1984;  101 847-851
• 9 Girela E, Villanueva E, Hernandez-Cueto C, Luna J D. Comparison of the CAGE questionnaire versus some biochemical markers in the diagnosis of alcoholism.  Alcohol Alcohol. 1994;  29 337-343
• 10 Bradley K A, Bush K R, McDonell M B et al.. Screening for problem drinking: comparison of CAGE and AUDIT. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test.  J Gen Intern Med. 1998;  13 379-388
• 11 Saunders J B, Aasland O G, Babor T F et al.. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption-II.  Addiction. 1993;  88 791-804
• 12 Bush K, Kivlahan D R, McDonell M B et al.. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test.  Arch Intern Med. 1998;  158 1789-1795
• 13 Regier D A, Farmer M E, Rae D S et al.. Comorbidity of mental disorders with alcohol and other drug abuse. Results from the Epidemiologic Catchment Area (ECA) Study.  JAMA. 1990;  264 2511-2518
• 14 American Psychiatric Association .Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR), 4th ed. Washington, D.C.; American Psychiatric Association 2000
• 15 French S W, Nash J, Shitabata P et al.. Pathology of alcoholic liver disease. VA Cooperative Study Group 119.  Semin Liver Dis. 1993;  13 154-169
• 16 Teli M R, Day C P, Burt A D et al.. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver.  Lancet. 1995;  346 987-990
• 17 Mendenhall C L. Alcoholic hepatitis.  Clin Gastroenterol. 1981;  10 417-441
• 18 Cohen J A, Kaplan M M. The SGOT/SGPT ratio-an indicator of alcoholic liver disease.  Dig Dis Sci. 1979;  24 835-838
• 19 Sorbi D, Boynton J, Lindor K D. The ratio of aspartate aminotransferase to alanine aminotransferase: potential value in differentiating nonalcoholic steatohepatitis from alcoholic liver disease.  Am J Gastroenterol. 1999;  94 1018-1022
• 20 Williams A L, Hoofnagle J H. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis.  Gastroenterology. 1988;  95 734-739
• 21 Diehl A M, Potter J, Boitnott J et al.. Relationship between pyridoxal 5′-phosphate deficiency and aminotransferase levels in alcoholic hepatitis.  Gastroenterology. 1984;  86 632-636
• 22 Bell H, Tallaksen C M, Try K, Haug E. Carbohydrate-deficient transferrin and other markers of high alcohol consumption: a study of 502 patients admitted consecutively to a medical department.  Alcohol Clin Exp Res. 1994;  18 1103-1108
• 23 Stewart S H. Racial and ethnic differences in alcohol-associated aspartate aminotransferase and gamma-glutamyltransferase elevation.  Arch Intern Med. 2002;  162 2236-2239
• 24 Talley N J, Roth A, Woods J, Hench V. Diagnostic value of liver biopsy in alcoholic liver disease.  J Clin Gastroenterol. 1988;  10 647-650
• 25 MacSween. Alcoholic liver disease: morphological manifestations. Review by an international group.  Lancet. 1981;  1 707-711
• 26 Velt P M, Choy O G, Shimkin P M, Link R J. Transjugular liver biopsy in high-risk patients with hepatic disease.  Radiology. 1984;  153 91-93
• 27 Levin D M, Baker A L, Riddell R H et al.. Nonalcoholic liver disease. Overlooked causes of liver injury in patients with heavy alcohol consumption.  Am J Med. 1979;  66 429-434
• 28 Orrego H, Blake J E, Blendis L M, Medline A. Prognosis of alcoholic cirrhosis in the presence and absence of alcoholic hepatitis.  Gastroenterology. 1987;  92 208-214
• 29 Anderson S, Nevins C L, Green L K et al.. Assessment of liver histology in chronic alcoholics with and without hepatitis C virus infection.  Dig Dis Sci. 2001;  46 1393-1398
• 30 Tamai T, Seki T, Shiro T et al.. Effects of alcohol consumption on histological changes in chronic hepatitis C: a clinicopathological study.  Alcohol Clin Exp Res. 2000;  24(Suppl 4) 106S-111S
• 31 Mendenhall C L, Moritz T, Rouster S et al.. Epidemiology of hepatitis C among veterans with alcoholic liver disease. The VA Cooperative Study Group 275.  Am J Gastroenterol. 1993;  88 1022-1026
• 32 Mendenhall C L, Seeff L, Diehl A M et al.. Antibodies to hepatitis B virus and hepatitis C virus in alcoholic hepatitis and cirrhosis: their prevalence and clinical relevance. The VA Cooperative Study Group (No. 119).  Hepatology. 1991;  14 581-589
• 33 Corrao G, Carle F, Lepore A R et al.. Interaction between alcohol consumption and positivity for antibodies to hepatitis C virus on the risk of liver cirrhosis: a case-control study. Provincial Group for the Study of Chronic Liver Disease.  Eur J Epidemiol. 1992;  8 634-639
• 34 Tanaka T, Yabusako T, Yamashita T et al.. Contribution of hepatitis C virus to the progression of alcoholic liver disease.  Alcohol Clin Exp Res. 2000;  24(Suppl 4) 112S-116S
• 35 Worner T M, Lieber C S. Perivenular fibrosis as precursor lesion of cirrhosis.  JAMA. 1985;  254 627-630
• 36 Conigrave K M, Saunders J B, Whitfield J B. Diagnostic tests for alcohol consumption.  Alcohol Alcohol. 1995;  30 13-26
• 37 Stibler H, Borg S. Carbohydrate composition of serum transferrin in alcoholic patients.  Alcohol Clin Exp Res. 1986;  10 61-64
• 38 Storey E L, Mack U, Powell L W, Halliday J W. Use of chromatofocusing to detect a transferrin variant in serum of alcoholic subjects.  Clin Chem. 1985;  31 1543-1545
• 39 Conigrave K M, Degenhardt L J, Whitfield J B et al.. CDT, GGT, and AST as markers of alcohol use: the WHO/ISBRA collaborative project.  Alcohol Clin Exp Res. 2002;  26 332-339
• 40 Xin Y, Rosman A S, Lasker J M, Lieber C S. Measurement of carbohydrate-deficient transferrin by isoelectric focusing/western blotting and by micro anion-exchange chromatography/radioimmunoassay: comparison of diagnostic accuracy.  Alcohol Alcohol. 1992;  27 425-433
• 41 Nalpas B, Hispard E, Thepot V et al.. A comparative study between carbohydrate-deficient transferrin and gamma-glutamyltransferase for the diagnosis of excessive drinking in a liver unit.  J Hepatol. 1997;  27 1003-1008
• 42 Salmela K S, Laitinen K, Nystrom M, Salaspuro M. Carbohydrate-deficient transferrin during 3 weeks' heavy alcohol consumption.  Alcohol Clin Exp Res. 1994;  18 228-230
• 43 Bisson J I, Milford-Ward A. A comparison of carbohydrate deficient transferrin with other markers of alcohol misuse in male soldiers under the age of thirty.  Alcohol Alcohol. 1994;  29 315-321
• 44 Anton R F, Moak D H, Latham P. Carbohydrate-deficient transferrin as an indicator of drinking status during a treatment outcome study.  Alcohol Clin Exp Res. 1996;  20 841-846
• 45 Rosman A S, Basu P, Galvin K, Lieber C S. Utility of carbohydrate-deficient transferrin as a marker of relapse in alcoholic patients.  Alcohol Clin Exp Res. 1995;  19 611-616
• 46 Huseby N E, Bjordal E, Nilssen O, Barth T. Utility of biological markers during outpatient treatment of alcohol-dependent subjects: carbohydrate-deficient transferrin responds to moderate changes in alcohol consumption.  Alcohol Clin Exp Res. 1997;  21 1343-1346
• 47 Niemela O, Sorvajarvi K, Blake J E, Israel Y. Carbohydrate-deficient transferrin as a marker of alcohol abuse: relationship to alcohol consumption, severity of liver disease, and fibrogenesis.  Alcohol Clin Exp Res. 1995;  19 1203-1208
• 48 Halm U, Tannapfel A, Mossner J, Berr F. Relative versus absolute carbohydrate-deficient transferrin as a marker of alcohol consumption in patients with acute alcoholic hepatitis.  Alcohol Clin Exp Res. 1999;  23 1614-1618
• 49 Heinemann A, Sterneck M, Kuhlencordt R et al.. Carbohydrate-deficient transferrin: diagnostic efficiency among patients with end-stage liver disease before and after liver transplantation.  Alcohol Clin Exp Res. 1998;  22 1806-1812
• 50 Kwoh-Gain I, Fletcher L M, Price J et al.. Desialylated transferrin and mitochondrial aspartate aminotransferase compared as laboratory markers of excessive alcohol consumption.  Clin Chem. 1990;  36 841-845
• 51 Fletcher L M, Kwoh-Gain I, Powell E E et al.. Markers of chronic alcohol ingestion in patients with nonalcoholic steatohepatitis: an aid to diagnosis.  Hepatology. 1991;  13 455-459
• 52 Stadheim L M, O'Brien J F, Lindor K D et al.. Value of determining carbohydrate-deficient transferrin isoforms in the diagnosis of alcoholic liver disease.  Mayo Clin Proc. 2003;  78 703-707
• 53 Fagerberg B, Agewall S, Berglund A et al.. Is carbohydrate-deficient transferrin in serum useful for detecting excessive alcohol consumption in hypertensive patients?.  Clin Chem. 1994;  40 2057-2063
• 54 Stauber R E, Stepan V, Trauner M et al.. Evaluation of carbohydrate-deficient transferrin for detection of alcohol abuse in patients with liver dysfunction.  Alcohol Alcohol. 1995;  30 171-176
• 55 Sorvajarvi K, Blake J E, Israel Y, Niemela O. Sensitivity and specificity of carbohydrate-deficient transferrin as a marker of alcohol abuse are significantly influenced by alterations in serum transferrin: comparison of two methods.  Alcohol Clin Exp Res. 1996;  20 449-454
• 56 Perret R, Froehlich F, Lavanchy D et al.. Is carbohydrate-deficient transferrin a specific marker for alcohol abuse? A study in patients with chronic viral hepatitis.  Alcohol Clin Exp Res. 1997;  21 1337-1342
• 57 DiMartini A, Day N, Lane T et al.. Carbohydrate deficient transferrin in abstaining patients with end-stage liver disease.  Alcohol Clin Exp Res. 2001;  25 1729-1733
• 58 Huseby N E, Nilssen O, Erfurth A et al.. Carbohydrate-deficient transferrin and alcohol dependency: variation in response to alcohol intake among different groups of patients.  Alcohol Clin Exp Res. 1997;  21 201-205
• 59 Lof K, Seppa K, Itala L et al.. Carbohydrate-deficient transferrin as an alcohol marker among female heavy drinkers: a population-based study.  Alcohol Clin Exp Res. 1994;  18 889-894
• 60 Agelink M W, Dirkes-Kersting A, Zeit T et al.. Sensitivity of carbohydrate-deficient transferrin (CDT) in relation to age and duration of abstinence.  Alcohol Alcohol. 1998;  33 164-167
• 61 Anttila P, Jarvi K, Latvala J et al.. Diagnostic characteristics of different carbohydrate-deficient transferrin methods in the detection of problem drinking: effects of liver disease and alcohol consumption.  Alcohol Alcohol. 2003;  38 415-420
• 62 Davis V E, Brown H, Huff J A, Cashaw J L. The alteration of serotonin metabolism to 5-hydroxytryptophol by ethanol ingestion in man.  J Lab Clin Med. 1967;  69 132-140
• 63 Voltaire A, Beck O, Borg S. Urinary 5-hydroxytryptophol: a possible marker of recent alcohol consumption.  Alcohol Clin Exp Res. 1992;  16 281-285
• 64 Ponnio M, Alho H, Heinala P et al.. Serum and saliva levels of sialic acid are elevated in alcoholics.  Alcohol Clin Exp Res. 1999;  23 1060-1064
• 65 Sillanaukee P, Ponnio M, Seppa K. Sialic acid: new potential marker of alcohol abuse.  Alcohol Clin Exp Res. 1999;  23 1039-1043
• 66 Hernandez-Munoz R, Baraona E, Blacksberg I, Lieber C S. Characterization of the increased binding of acetaldehyde to red blood cells in alcoholics.  Alcohol Clin Exp Res. 1989;  13 654-659
• 67 Nalpas B, Vassault A, Charpin S et al.. Serum mitochondrial aspartate aminotransferase as a marker of chronic alcoholism: diagnostic value and interpretation in a liver unit.  Hepatology. 1986;  6 608-614
• 68 Hultberg B, Isaksson A, Joelsson B et al.. Pattern of serum beta-hexosaminidase in liver cirrhosis.  Scand J Gastroenterol. 1983;  18 877-880
• 69 Hultberg B, Isaksson A, Jansson L. Beta-hexosaminidase in serum from patients with cirrhosis and cholestasis.  Enzyme. 1981;  26 296-300
• 70 Hultberg B, Braconier J H, Isaksson A, Jansson L. Beta-hexosaminidase level in serum from patients with viral hepatitis as a measure of reticuloendothelial function.  Scand J Infect Dis. 1981;  13 241-245
• 71 Uppal R, Rosman A, Hernandez R et al.. Effects of liver disease on red blood cell acetaldehyde in alcoholics and non-alcoholics.  Alcohol Alcohol Suppl. 1991;  1 323-326
• 72 Barr A. Drink: A Social History of America. New York; Carroll and Graf 1999
• 73 Markel H. Treatment for addiction meets barriers in the doctor's office. The New York Times December 21 2003
• 74 Kahan M, Wilson L, Becker L. Effectiveness of physician-based interventions with problem drinkers: a review.  Can Med Assoc J. 1995;  152 851-859
• 75 Isaacson J H, Schorling J B. Screening for alcohol problems in primary care.  Med Clin North Am. 1999;  83 1547-1563
• 76 Whitlock E P. Alcohol screening in primary care.  BMJ. 2003;  327 E263-E264
• 77 Leevy C M. Fatty liver: a study of 270 patients with biopsy proven fatty liver and review of the literature.  Medicine (Baltimore). 1962;  41 249-276
• 78 Alexander J F, Lischner M W, Galambos J T. Natural history of alcoholic hepatitis. II. The long-term prognosis.  Am J Gastroenterol. 1971;  56 515-525
• 79 Galambos J T. Natural history of alcoholic hepatitis. 3. Histological changes.  Gastroenterology. 1972;  63 1026-1035
• 80 Pares A, Caballeria J, Bruguera M et al.. Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage.  J Hepatol. 1986;  2 33-42
• 81 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;  44 406-420
• 82 Chedid A, Mendenhall C L, Gartside P et al.. Prognostic factors in alcoholic liver disease. VA Cooperative Study Group.  Am J Gastroenterol. 1991;  86 210-216
• 83 Galambos J T. Alcoholic hepatitis: its therapy and prognosis.  Prog Liver Dis. 1972;  4 567-588
• 84 Pessione F, Ramond M J, Peters L et al.. Five-year survival predictive factors in patients with excessive alcohol intake and cirrhosis. Effect of alcoholic hepatitis, smoking and abstinence.  Liver Int. 2003;  23 45-53
• 85 Stewart S, Jones D, Day C P. Alcoholic liver disease: new insights into mechanisms and preventative strategies.  Trends Mol Med. 2001;  7 408-413
• 86 Raynard B, Balian A, Fallik D et al.. Risk factors of fibrosis in alcohol-induced liver disease.  Hepatology. 2002;  35 635-638
• 87 Capron J P, Delamarre J, Dupas J L et al.. Fasting in obesity: another cause of liver injury with alcoholic hyaline?.  Dig Dis Sci. 1982;  27 265-268
• 88 Lieber C. Medical and Nutritional Complications of Alcholism. New York; Plenum 1992: 97-103
• 89 Barak A J, Beckenhauer H C, Badakhsh S, Tuma D J. The effect of betaine in reversing alcoholic steatosis.  Alcohol Clin Exp Res. 1997;  21 1100-1102
• 90 Ji C, Kaplowitz N. Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice.  Gastroenterology. 2003;  124 1488-1499
• 91 Lieber C S. S-adenosyl-L-methionine: its role in the treatment of liver disorders.  Am J Clin Nutr. 2002;  76 1183S-1187S
• 92 Sidransky H, Farber E. Liver choline oxidase activity in man and in several species of animals.  Arch Biochem Biophys. 1960;  87 129-133
• 93 Kharbanda K K, Rogers II D D, Mailliard M E et al.. The comparative effects of betaine and S-adenosylmethionine on ethanol-induced changes of methionine metabolism and hepatic steatosis.  Biochim Biophys Acta. 2004;  , (in press)
• 94 Abdelmalek M F, Angulo P, Jorgensen R A et al.. Betaine, a promising new agent for patients with nonalcoholic steatohepatitis: results of a pilot study.  Am J Gastroenterol. 2001;  96 2711-2717
• 95 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
• 96 Lohr R H. Treatment of alcohol withdrawal in hospitalized patients.  Mayo Clin Proc. 1995;  70 777-782
• 97 Long C G, Williams M, Hollin C R. Treating alcohol problems: a study of programme effectiveness and cost effectiveness according to length and delivery of treatment.  Addiction. 1998;  93 561-571
• 98 Hoffmann N G, Miller N S. Perspectives of effective treatment for alcohol and drug disorders.  Psychiatr Clin North Am. 1993;  16 127-140
• 99 Weisner C, Ray G T, Mertens J R, Satre D D, Moore C. Short-term alcohol and drug treatment outcomes predict long-term outcome.  Drug Alcohol Depend. 2003;  71 281-294
• 100 Hilton M E, Maisto S A, Conigliaro J et al.. Improving alcoholism treatment across the spectrum of services.  Alcohol Clin Exp Res. 2001;  25 128-135
• 101 Graham R, Wodak A D, Whelan G. New pharmacotherapies for alcohol dependence.  Med J Aust. 2002;  177 103-107
• 102 Overman G P, Teter C J, Guthrie S K. Acamprosate for the adjunctive treatment of alcohol dependence.  Ann Pharmacother. 2003;  37 1090-1099
• 103 Weinrieb R M, Van Horn D H, McLellan A T et al.. Drinking behavior and motivation for treatment among alcohol-dependent liver transplant candidates.  J Addict Dis. 2001;  20 105-119
• 104 Kandel D B, Huang F Y, Davies M. Comorbidity between patterns of substance use dependence and psychiatric syndromes.  Drug Alcohol Depend. 2001;  64 233-241
• 105 Serra M A, Escudero A, Rodriguez F et al.. Effect of hepatitis C virus infection and abstinence from alcohol on survival in patients with alcoholic cirrhosis.  J Clin Gastroenterol. 2003;  36 170-174
• 106 Tabone M, Sidoli L, Laudi C et al.. Alcohol abstinence does not offset the strong negative effect of lifetime alcohol consumption on the outcome of interferon therapy.  J Viral Hepat. 2002;  9 288-294
• 107 Lieber C S, Weiss D G, Groszmann R et al.. I. Veterans Affairs Cooperative Study of Polyenylphosphatidylcholine in Alcoholic Liver Disease: effects on drinking behavior by nurse/physician teams.  Alcohol Clin Exp Res. 2003;  27 1757-1764
• 108 Lieber C S, Weiss D G, Groszmann R et al.. Veterans Affairs Cooperative Study of Polyenylphosphatidylcholine in Alcoholic Liver Disease.  Alcohol Clin Exp Res. 2003;  27 1765-1772
• 109 Goldberg S, Mendenhall C, Anderson S et al.. VA Cooperative Study on Alcoholic Hepatitis. IV. The significance of clinically mild alcoholic hepatitis-describing the population with minimal hyperbilirubinemia.  Am J Gastroenterol. 1986;  81 1029-1034
• 110 Imperiale T F, McCullough A J. Do corticosteroids reduce mortality from alcoholic hepatitis? A meta-analysis of the randomized trials.  Ann Intern Med. 1990;  113 299-307
• 111 Schenker S. Alcoholic liver disease: evaluation of natural history and prognostic factors.  Hepatology. 1984;  4(Suppl 1) 36S-43S
• 112 Porter H P, Simon F R, Pope C E et al.. Corticosteroid therapy in severe alcoholic hepatitis.  N Engl J Med. 1971;  284 1250-1255
• 113 Helman R A, Temko M H, Nye S W, Fallon H J. Alcoholic hepatitis. Natural history and evaluation of prednisolone therapy.  Ann Intern Med. 1971;  74 311-321
• 114 Blitzer B L, Mutchnick M G, Joshi P H et al.. Adrenocorticosteroid therapy in alcoholic hepatitis. A prospective, double-blind randomized study.  Am J Dig Dis. 1977;  22 477-484
• 115 Lesesne H R, Bozymski E M, Fallon H J. Treatment of alcoholic hepatitis with encephalopathy. Comparison of prednisolone with caloric supplements.  Gastroenterology. 1978;  74 169-173
• 116 Maddrey W C, Boitnott J K, Bedine M S et al.. Corticosteroid therapy of alcoholic hepatitis.  Gastroenterology. 1978;  75 193-199
• 117 Campra J L, Hamlin EM Jr, Kirshbaum R J et al.. Prednisone therapy of acute alcoholic hepatitis. Report of a controlled trial.  Ann Intern Med. 1973;  79 625-631
• 118 Depew W, Boyer T, Omata M et al.. Double-blind controlled trial of prednisolone therapy in patients with severe acute alcoholic hepatitis and spontaneous encephalopathy.  Gastroenterology. 1980;  78 524-529
• 119 Theodossi A, Eddleston A L, Williams R. Controlled trial of methylprednisolone therapy in severe acute alcoholic hepatitis.  Gut. 1982;  23 75-79
• 120 Mendenhall C L, Anderson S, Garcia-Pont P et al.. Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone.  N Engl J Med. 1984;  311 1464-1470
• 121 Carithers Jr R L, Herlong H F, Diehl A M et al.. Methylprednisolone therapy in patients with severe alcoholic hepatitis. A randomized multicenter trial.  Ann Intern Med. 1989;  110 685-690
• 122 Ramond M J, Poynard T, Rueff B et al.. A randomized trial of prednisolone in patients with severe alcoholic hepatitis.  N Engl J Med. 1992;  326 507-512
• 123 Cabr 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
• 124 Christensen E, Gluud C. Glucocorticoids are ineffective in alcoholic hepatitis: a meta-analysis adjusting for confounding variables.  Gut. 1995;  37 113-118
• 125 Mathurin P, Mendenhall C L, Carithers R L et al.. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis (AH): individual data analysis of the last three randomized placebo controlled double blind trials of corticosteroids in severe AH.  J Hepatol. 2002;  36 480-487
• 126 Powell L W, Axelsen E. Corticosteroids in liver disease: studies on the biological conversion of prednisone to prednisolone and plasma protein binding.  Gut. 1972;  13 690-696
• 127 O'Keefee C, McCormick P A. Severe acute alcoholic hepatitis: an audit of medical treatment.  Ir Med J. 2002;  95 108-109
• 128 Tilg H, Diehl A M. Cytokines in alcoholic and nonalcoholic steatohepatitis.  N Engl J Med. 2000;  343 1467-1476
• 129 Ramadori G, Armbrust T. Cytokines. In: Diehl AM, Strain AJ Liver Growth and Repair. New York; Kluwer 1998: 283-294
• 130 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
• 131 Hill D B, Marsano L, Cohen D et al.. Increased plasma interleukin-6 concentrations in alcoholic hepatitis.  J Lab Clin Med. 1992;  119 547-552
• 132 Hanck C, Rossol S, Bocker U et al.. Presence of plasma endotoxin is correlated with tumour necrosis factor receptor levels and disease activity in alcoholic cirrhosis.  Alcohol Alcohol. 1998;  33 606-608
• 133 Starkel P, Bishop K, Horsmans Y, Strain A J. Expression and DNA-binding activity of signal transducer and activator of transcription 3 in alcoholic cirrhosis compared to normal liver and primary biliary cirrhosis in humans.  Am J Pathol. 2003;  162 587-596
• 134 Yin M, Wheeler M D, Kono H et al.. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice.  Gastroenterology. 1999;  117 942-952
• 135 Iimuro Y, Gallucci R M, Luster M I et al.. Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inflammation caused by chronic exposure to ethanol in the rat.  Hepatology. 1997;  26 1530-1537
• 136 McHutchison J G, Runyon B A, Draguesku J O et al.. Pentoxifylline may prevent renal impairment (hepatorenal syndrome) in severe acute alcoholic hepatitis.  Hepatology. 1991;  14 96A
• 137 Akriviadis E, Botla R, Briggs W et al.. Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial.  Gastroenterology. 2000;  119 1637-1648
• 138 Tilg H, Jalan R, Kaser A et al.. Anti-tumor necrosis factor-alpha monoclonal antibody therapy in severe alcoholic hepatitis.  J Hepatol. 2003;  38 419-425
• 139 Spahr L, Rubbia-Brandt L, Frossard J L et al.. Combination of steroids with infliximab or placebo in severe alcoholic hepatitis: a randomized controlled pilot study.  J Hepatol. 2002;  37 448-455
• 140 Narayanan Menon K V, Stadheim L, Kamath P S et al.. A Pilot Study of the Safety and Tolerability of Etanercept in Patients with Alcoholic Hepatitis.  Am J Gastroenterol. 2004;  99 255-260
• 141 Poynard T, Thabut D, Chryssostalis A et al.. Anti-tumor necrosis factor-alpha therapy in severe alcoholic hepatitis: are large randomized trials still possible?.  J Hepatol. 2003;  38 518-520
• 142 Berger K, Ajani U A, Kase C S et al.. Light-to-moderate alcohol consumption and risk of stroke among U.S. male physicians.  N Engl J Med. 1999;  341 1557-1564
• 143 Jackson V A, Sesso H D, Buring J E, Gaziano J M. Alcohol consumption and mortality in men with preexisting cerebrovascular disease.  Arch Intern Med. 2003;  163 1189-1193
• 144 Volpato S, Pahor M, Ferrucci L et al.. Relationship of alcohol intake with inflammatory markers and plasminogen activator inhibitor-1 in well-functioning older adults: the Health, Aging, and Body Composition study.  Circulation. 2004;  109 607-612
• 145 Tsukamoto H, Lu S C. Current concepts in the pathogenesis of alcoholic liver injury.  FASEB J. 2001;  15 1335-1349
• 146 Arteel G E. Oxidants and antioxidants in alcohol-induced liver disease.  Gastroenterology. 2003;  124 778-790
• 147 McKim S E, Gabele E, Isayama F et al.. Inducible nitric oxide synthase is required in alcohol-induced liver injury: studies with knockout mice.  Gastroenterology. 2003;  125 1834-1844
• 148 Mezey E, Potter J J, Rennie-Tankersley L et al.. A randomized placebo controlled trial of vitamin E for alcoholic hepatitis.  J Hepatol. 2004;  40 40-46
• 149 Mato J M, Camara J, Fernandez D P et al.. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial.  J Hepatol. 1999;  30 1081-1089
• 150 Torres L, Garcia-Trevijano E R, Rodriguez J A et al.. Induction of TIMP-1 expression in rat hepatic stellate cells and hepatocytes: a new role for homocysteine in liver fibrosis.  Biochim Biophys Acta. 1999;  1455 12-22
• 151 Rappaport AM, Khanna JM, Israel Y, Kalant H Liver Architecture and Microcirculation. Alcoholic Liver Pathology. Toronto; House of Lind 1975
• 152 Kaplowitz N. Propylthiouracil treatment for alcoholic hepatitis: should it and does it work?.  Gastroenterology. 1982;  82 1468-1471
• 153 Bernstein J, Videla L, Israel Y. Hormonal influences in the development of the hypermetabolic state of the liver produced by chronic administration of ethanol.  J Pharmacol Exp Ther. 1975;  192 583-591
• 154 Israel Y, Kalant H, Orrego H et al.. Experimental alcohol-induced hepatic necrosis: suppression by propylthiouracil.  Proc Natl Acad Sci USA. 1975;  72 1137-1141
• 155 Orrego H, Blake J E, Blendis L M et al.. Long-term treatment of alcoholic liver disease with propylthiouracil.  N Engl J Med. 1987;  317 1421-1427
• 156 Halle P, Pare P, Kaptein E et al.. Double-blind, controlled trial of propylthiouracil in patients with severe acute alcoholic hepatitis.  Gastroenterology. 1982;  82 925-931
• 157 Orrego H, Kalant H, Israel Y et al.. Effect of short-term therapy with propylthiouracil in patients with alcoholic liver disease.  Gastroenterology. 1979;  76 105-115
• 158 Rambaldi A, Gluud C. Propylthiouracil for alcoholic liver disease (Cochrane Review). In: The Cochrane Library issue 3 Chichester, UK; John Wiley & Sons 2004
• 159 Maddrey W C. Is therapy with testosterone or anabolic-androgenic steroids useful in the treatment of alcoholic liver disease?.  Hepatology. 1986;  6 1033-1035
• 160 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
• 161 Rambaldi A, Iaquinto G, Gluud C. Anabolic-androgenic steroids for alcoholic liver disease: a Cochrane Review.  Am J. Gastroenterol. 2002;  97 1674-1684
• 162 Ferenci P, Dragosics B, Dittrich H et al.. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver.  J Hepatol. 1989;  9 105-113
• 163 Pares A, Planas R, Torres M et al.. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial.  J Hepatol. 1998;  28 615-621
• 164 Kershenobich D, Vargas F, Garcia-Tsao G et al.. Colchicine in the treatment of cirrhosis of the liver.  N Engl J Med. 1988;  318 1709-1713
• 165 Rambaldi A, Gluud C. Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis.  Liver. 2001;  21 129-136
• 166 Bird G, Lau J Y, Koskinas J et al.. Insulin and glucagon infusion in acute alcoholic hepatitis: a prospective randomized controlled trial.  Hepatology. 1991;  14 1097-1101
• 167 Trinchet J C, Balkau B, Poupon R E et al.. Treatment of severe alcoholic hepatitis by infusion of insulin and glucagon: a multicenter sequential trial.  Hepatology. 1992;  15 76-81
• 168 Friedman S L. Liver fibrosis-from bench to bedside.  J Hepatol. 2003;  38(Suppl 1) S38-S53
• 169 Murphy F, Arthur M, Iredale J. Developing strategies for liver fibrosis treatment.  Expert Opin Investig Drugs. 2002;  11 1575-1585
• 170 Enomoto N, Takei Y, Hirose M et al.. Thalidomide prevents alcoholic liver injury in rats through suppression of Kupffer cell sensitization and TNF-alpha production.  Gastroenterology. 2002;  123 291-300
• 171 Song Z, Joshi-Barve S, Barve S, McClain C J. Advances in alcoholic liver disease.  Curr Gastroenterol Rep. 2004;  6 71-76
• 172 Havel P J. Update on adipocyte hormones: regulation of energy balance and carbohydrate/lipid metabolism.  Diabetes. 2004;  53(Suppl 1) S143-S151
• 173 Xu A, Wang Y, Keshaw H et al.. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice.  J Clin Invest. 2003;  112 91-100