Definition, incidence, and diagnosis
Alcoholic hepatitis is a clinical syndrome, i.e. recent onset of jaundice and/or ascites in a patient with ongoing alcohol misuse. Historically, it was referred to as “acute alcoholic hepatitis”. Although the clinical presentation may present abruptly, the term “acute” is not recommended, since it is an exacerbation of an underlying chronic liver disease and usually follows an extended course. ASH, a disease defined histologically, is the predominant cause of this syndrome, which can also result from infection, massive micro-vesicular steatosis, stone migration, drug-induced liver injury, etc. ASH is defined by the coexistence of steatosis, hepatocyte ballooning, and an inflammatory infiltrate with PMNs. The lesions defining alcoholic steatohepatitis do not differ in essence from those described in non-alcoholic steatohepatitis. ASH, however, is usually associated with more severe clinical course and histological lesions than NASH. Chronic alcoholism symptoms.
The annual incidence of ASH remains largely unknown. A retrospective Danish study based on diagnosis codes estimated the incidence to range from 24 to 46 per million in women and men, respectively . Concerning its prevalence, a large study using systematic biopsies in 1604 alcoholic patients, symptomatic or not, showed the prevalence of ASH to be 20% of cases . In symptomatic patients including those with decompensated liver disease, the prevalence of ASH is not well known, partly because most centers rely on clinical criteria and do not consider transjugular liver biopsy as a routine practice in the management of patients with decompensated ALD. Relying only on clinical criteria carries a 10–50% risk of wrongly classifying patients with or without ASH [ , ,  ]. In a recent prospective cohort study of 250 patients, histological proven severe ASH was observed in 6% of the patients with a chronic hepatic decompensation and in 25% of the patients who developed an acute-on-chronic liver failure during admission .
Progressive jaundice is the main presenting feature of symptomatic ASH. It may be associated with fever with or without infection, weight loss and malnutrition, and a large tender liver. In severe cases, ASH may induce liver decompensation with ascites, encephalopathy, and gastrointestinal bleeding. With respect to biological tests, AST levels are typically elevated to 2–6 times the upper limit of the normal range with AST/ALT ratio greater than 2 and increased bilirubinemia and neutrophilia are also frequently observed. Depending upon the severity, serum albumin may be decreased, prothombin time prolonged and the international normalized ratio (INR) may be elevated. Patients with severe forms of ASH are prone to develop bacterial infection and acute renal failure due to Type 1 hepatorenal syndrome .
Prognostic models in alcoholic steatohepatitis
Prognostic models have been designed to identify patients with ASH at high risk of early death 1–2 months after hospitalization. The Maddrey discriminant function (DF) was the first score to be developed and remains the most widely used. Severe forms of ASH are defined as DF ⩾32 [ ,  ]. In the absence of treatment, the 1-month spontaneous survival of patients with a DF ⩾32 has fluctuated between 50% and 65% [ ,  ].
Other prognostic scores such the MELD (Model for End-Stage Liver Disease), the GAHS (Glasgow ASHScore) and the ABIC score (age, serum Bilirubin, INR, and serum Creatinine score) have been proposed in the setting of ASH. The initial studies testing those scores suggest higher diagnostic accuracy in predicting 28-day and 90-day outcome than DF, but external validation is still required and the proposed cut-off of those scores need to be tested outside the initial population of their development [ , , ,  ].
It is important to stress that actual definition of severe forms is only based on two categories (severe versus non-severe) and early mortality risk. However, a proportion patients classified as having “non-severe ASH” die at later time points (i.e. up to 6 months). The ABIC score classified patients according to low, intermediate and high risk of death . Such classification will permit the evaluation of drugs and help to calculate the sample size for such purpose.
Early improvement in liver function has a major impact on short-term mortality . Several studies have demonstrated the utility of repeated testing and calculation of prognostic scores [ , ,  ]. For example, a ⩾2 points change in the MELD score in the first week has been shown to predict in-hospital mortality . A similar observation was obtained with the Lille score which includes the reduction in serum bilirubin at day 7 . Based on a recent meta-analysis of individual patient data using 2 new cut-offs of the Lille score, three prognostic groups predicting the 6-month survival could be defined .
Management of ASH
Regardless of the severity, abstinence is the cornerstone of therapy and early management of alcohol abuse or dependence is warranted in all patients with ASH. Malnutrition is frequent and nutrition status should be evaluated. Considering the potential risk of Wernicke's encephalopathy, supplementation with B-complex vitamins is recommended. Independent from hepatic encephalopathy, a daily protein intake of 1.5 g/kg of body weight should be ensured. Liposoluble vitamins deficiency should be compensated.
Patients with symptomatic forms of ASH often develop acute renal failure which negatively impacts survival . The most frequent causes of acute renal failure are Type 1 hepatorenal syndrome and tubular necrosis whereas glomerulonephritis or interstitial nephritis are uncommon . Severe forms of ASH should be considered as a risk factor of radiocontrast-induced nephropathy. Measures aimed at preventing the development of renal failure are recommended. They include volume expansion if needed and early treatment of hepatorenal syndrome.
Infections are frequent and difficult to diagnose in these patients since SIRS criteria is common at admission and could reflect either the inflammatory state associated with the ASH episode or an ongoing bacterial infection. Systematic body fluid sampling and close clinical monitoring are advised for early detection of infection. In the absence of scientific evidence, criteria for initiating empirical antibiotic administration, although it is widely used, remain debated. In patients with severe ASH, infection screening at admission is particularly warranted because a quarter of them are infected at admission . Patients with severe ASH and clinical or biological deterioration during their hospital stay disclose a even higher risk of infection and should be screened repeatedly.
Specific therapy in severe forms of alcoholic steatohepatitis
The following recommendations apply only to severe forms of ASH, as defined using the above prognostic scores predicting a high risk of early death (Table 3, Fig. 2).
Meta-analyses of the literature yielded inconsistent results than can be mainly attributed to the wide variations in disease severity . Three meta-analyses concluded that the survival effect of corticosteroids was restricted to severe disease [ , ,  ], whereas Cochrane meta-analyses questioned the efficacy of corticosteroids in AH [ ,  ]. The most recent Cochrane meta-analysis reported that corticosteroids significantly reduced mortality in the subgroup of trials that enrolled patients with a DF of at least 32 or hepatic encephalopathy . Analysis of individual data from the five most recent randomized controlled trials [ , , , ,  ] showed that patients allocated to corticosteroid treatment had higher 28-day survival than patients allocated to non-corticosteroid treatment .
Most studies indicate that only a limited proportion of patients with severe forms of ASH benefit from corticosteroids. Thus, early identification of non-responders to corticosteroids is important to define stopping rules  and limit unnecessary exposure . For example, after 7 days on corticosteroids, a Lille score above 0.45 predicts poor response . In poor responders, the interruption of corticosteroids is recommended particularly in those classified as null responders (Lille score >,0.56) . In poor responders, an early switch to pentoxifylline  or the use of a molecular adsorbent recirculating system (MARS) appears not to modify the outcome. Novel therapies are urgently needed for poor responders. In these patients, early liver transplantation may be considered after a careful selection process .
The applicability of corticosteroid therapy is limited by concerns about heightened risks of sepsis and gastrointestinal hemorrhage. Patients with gastrointestinal bleeding  or hepatorenal syndrome may be less responsive to steroid treatment than patients without these complications. In such circumstances, the outcome of patients may be related to these complications rather than to ASH itself. Up to now, in severe AH, infection has classically been viewed as a contraindication for corticosteroid treatment, although specific data are lacking. In patients with sepsis, pentoxifylline can be considered as a first line therapy. However, a recent study suggests that corticosteroid treatment may not be precluded in patients with infection after appropriate antibiotic therapy .
Pentoxifylline has been evaluated in patients with ASH for its antioxidant and anti-TNF properties. When compared to placebo, patients with severe AH (DF ⩾32) treated with pentoxifylline exhibited a higher 6-month survival. This survival benefit was not accompanied by significant changes in liver function but related to a marked reduction in the incidence of hepatorenal syndrome . One subsequent randomized controlled trial in patients with cirrhosis related or not with ALD also supported the preventive effect of pentoxifylline on hepatorenal syndrome . However, a sensitivity analysis restricted to the subgroup of patients with severe AH (DF ⩾32), failed to show a significant difference in survival between the pentoxifylline and placebo treated patients.
One study comparing pentoxifylline to corticosteroids observed better outcome in pentoxifylline-treated patients, which was related to prevention of hepatorenal syndrome . A recent, large randomized controlled trial of 270 patients with severe AH testing the combination of prednisolone and pentoxifylline (PTX) failed to show any benefit over corticosteroids alone .
A pilot randomized study in patients with severe ASH showed that single dose infliximab in combination with corticosteroids was well tolerated and associated with a significant improvement in Maddrey's score at day 28 . However, the size of this study did not allow comparison with a control group . However, the effectiveness of anti-TNFα was not confirmed in two randomized controlled trials testing multiple doses of infliximab  or etanercept . In fact, anti-TNFα treatment was associated with a higher probability of severe infections and deaths. It may be speculated that repeated or excessive TNF blockade negatively affects liver regeneration.
N-acetylcysteine is an antioxidant substance and replenishes glutathione stores in hepatocytes. In a randomized controlled trial of N-acetylcysteine alone versus placebo there was no evidence of a significant effect . In another randomized trial, N-acetylcysteine alone was inferior to corticosteroids in terms of short-term survival . More recently, a randomized controlled trial observed that patients treated with combination therapy (corticosteroids and N-acetylcysteine) had better 1-month survival than patients treated with corticosteroids alone . The rates of hepatorenal syndrome and of infection were lower in patients treated with corticosteroids and N-acetylcysteine. However, there was no significant difference in survival between the two groups at 6-months, the primary planned end point. Therefore, corticosteroids and N-acetylcysteine may have synergistic effects. This strategy and the question of optimal duration of N-acetylcysteine administration should be evaluated in additional studies.
Malnutrition due to impaired caloric intake and increased catabolism is frequent in patients with ASH. The recommended protein-caloric intake is often difficult to achieve orally in a significant proportion of patients with ASH.
A randomized controlled trial comparing enteral nutrition versus corticosteroids did not show any difference in 28-day mortality rate . However, deaths occurred earlier with enteral nutrition whereas steroid therapy was associated with a higher mortality rate in the weeks following the treatment period. Enteral nutrition probably deserves to be tested in combination with corticosteroids.
There are no randomized studies evaluating extracorporeal liver supports, although pilot studies reported improvement in circulatory disturbances, liver, and renal parameters. None of these studies have a sufficient sample size to draw any conclusions regarding the use of these systems as a therapeutic option in patients with severe forms of ASH .
Three randomized controlled trials did not observe significant effects of propylthiouracil on short-term survival in patients with ASH [ , ,  ]. Two studies did not observe any effect of colchicine on short-term survival [ ,  ]. Thus, evaluation of propylthiouracil or colchicine is no longer recommended in future studies evaluating short-term survival.
Need for future studies
The treatment of ASH remains controversial and is one of the main challenges in ALD . Short-term survival has been the primary outcome of studies evaluating therapy in severe forms of ASH. However, assuming a one or two-sided type I error ⩽0.05 and a power ⩾80%, this approach requires huge, unrealistic sample sizes. To overcome this limitation, it may be relevant to consider alternative end points, including early markers of poor outcome and/or combinations of criteria.
Little therapeutic information has been collected in patients with intermediate risk of death who are currently exempt from most clinical trials. Therefore, studies with appropriate designs and end points should focus on this patient population.
Suggestions for future studies
Development of non-invasive tools for the diagnosis of ASH is of major interest.
Use of primary end points other than short-term mortality should be encouraged to facilitate testing of new therapies in patients with ASH.
Future studies should also focus on patients with ASH of intermediate severity since they have substantial mortality at 6-months.
Translational studies should identify the molecular patterns, including liver inflammation and regeneration signaling, associated with differences in outcomes.
Shah, V.H. Alcoholic liver disease: the buzz may be gone, but the hangover remains. Hepatology. 2009, 51: 14831484
Gao, B. and Bataller, R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011, 141: 15721585
Guyatt, G.H., Oxman, A.D., Kunz, R., Falck-Ytter, Y., Vist, G.E., Liberati, A. et al. Going from evidence to recommendations. Br Med J. 2008, 336: 10491051
Rehm, J., Mathers, C., Popova, S., Thavorncharoensap, M., Teerawattananon, Y., and Patra, J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet. 2009, 373: 22232233
WHO, European Status Report on Alcohol and Health 2010. Copenhagen: WHO Regional Office for Europe, 2010.
Anderson, H.R. and Baumburg, B. Alcohol in Europe. A public health perspective. Institute of Alcohol Studies, London, 2006
Roulot, D., Costes, J.L., Buyck, J.F., Warzocha, U., Gambier, N., Czernichow, S. et al. Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 ,years. Gut. 2010, 60: 977984
Zatonski, W.A., Sulkowska, U., Manczuk, M., Rehm, J., Boffetta, P., Lowenfels, A.B. et al. Liver cirrhosis mortality in Europe, with special attention to Central and Eastern Europe. Eur Addict Res. 2010, 16: 193201
Leon DA, Collier T. Trends in mortality from liver cirrhosis in Europe in EASL meeting on alcoholic liver disease. Athens: 2010.
Leon, D.A. and McCambridge, J. Liver cirrhosis mortality rates in Britain from 1950 to 2002: an analysis of routine data. Lancet. 2006, 367: 5256
Parna, K. and Rahu, K. Dramatic increase in alcoholic liver cirrhosis mortality in Estonia in 19922008. Alcohol Alcohol. 2010, 45: 548551
Thomson, S.J., Westlake, S., Rahman, T.M., Cowan, M.L., Majeed, A., Maxwell, J.D. et al. Chronic liver disease an increasing problem: a study of hospital admission and mortality rates in England, 19792005, with particular reference to alcoholic liver disease. Alcohol Alcohol. 2008, 43: 416422
Welch, C., Harrison, D., Short, A., and Rowan, K. The increasing burden of alcoholic liver disease on United Kingdom critical care units: secondary analysis of a high quality clinical database. J Health Serv Res Policy. 2008, 13: 4044
Bell, G. and Cremona, A. Alcohol and death certification: a survey of current practice and attitudes. Br Med J (Clin Res Ed). 1987, 295: 95
Chronic alcoholic pancreatitis symptoms
Ramstedt, M. Alcohol consumption and liver cirrhosis mortality with and without mention of alcohol the case of Canada. Addiction. 2003, 98: 12671276
Zakhari, S. and Li, T.K. Determinants of alcohol use and abuse: impact of quantity and frequency patterns on liver disease. Hepatology. 2007, 46: 20322039
Popova, S., Rehm, J., Patra, J., and Zatonski, W. Comparing alcohol consumption in central and Eastern Europe to other European countries. Alcohol Alcohol. 2007, 42: 465473
Ramstedt, M. Per capita alcohol consumption and liver cirrhosis mortality in 14 European countries. Addiction. 2001, 96: S19S33
Mathurin, P. and Deltenre, P. Effect of binge drinking on the liver: an alarming public health issue?. Gut. 2009, 58: 613617
Rehm, J., Kanteres, F., and Lachenmeier, D.W. Unrecorded consumption, quality of alcohol and health consequences. Drug Alcohol Rev. 2010, 29: 426436
Gill, J., Tsang, C., Black, H., and Chick, J. Can part of the health damage linked to alcohol misuse in Scotland be attributable to the type of drink and its low price (by permitting a rapid rate of consumption)? A point of view. Alcohol Alcohol. 2010, 45: 398400
Lang, K., Vali, M., Szucs, S., Adany, R., and McKee, M. The composition of surrogate and illegal alcohol products in Estonia. Alcohol Alcohol. 2006, 41: 446450
McKee, M., Suzcs, S., Sarvary, A., Adany, R., Kiryanov, N., Saburova, L. et al. The composition of surrogate alcohols consumed in Russia. Alcohol Clin Exp Res. 2005, 29: 18841888
Szucs, S., Sarvary, A., McKee, M., and Adany, R. Could the high level of cirrhosis in central and Eastern Europe be due partly to the quality of alcohol consumed? An exploratory investigation. Addiction. 2005, 100: 536542
Gil, A., Polikina, O., Koroleva, N., McKee, M., Tomkins, S., and Leon, D.A. Availability and characteristics of nonbeverage alcohols sold in 17 Russian cities in 2007. Alcohol Clin Exp Res. 2009, 33: 7985
Lachenmeier, D.W., Samokhvalov, A.V., Leitz, J., Schoeberl, K., Kuballa, T., Linskiy, I.V. et al. The composition of unrecorded alcohol from eastern Ukraine: is there a toxicological concern beyond ethanol alone?. Food Chem Toxicol. 2010, 48: 28422847
Corrao, G., Rubbiati, L., Bagnardi, V., Zambon, A., and Poikolainen, K. Alcohol and coronary heart disease: a meta-analysis. Addiction. 2000, 95: 15051523
Klatsky, A.L. Alcohol and cardiovascular diseases. Expert Rev Cardiovasc Ther. 2009, 7: 499506
Corrao, G., Bagnardi, V., Zambon, A., and Torchio, P. Meta-analysis of alcohol intake in relation to risk of liver cirrhosis. Alcohol Alcohol. 1998, 33: 381392
Rehm, J., Taylor, B., Mohapatra, S., Irving, H., Baliunas, D., Patra, J. et al. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev. 2010, 29: 437445
Casswell, S. and Thamarangsi, T. Reducing harm from alcohol: call to action. Lancet. 2009, 373: 22472257
Anderson, P., Chisholm, D., and Fuhr, D.C. Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol. Lancet. 2009, 373: 22342246
Miller, W., Heather, N., and Hall, W. Calculating standard drink units: international comparisons. Br J Addict. 1991, 86: 4347
Saunders, J.B., Aasland, O.G., Babor, T.F., de la Fuente, J.R., and Grant, M. Development of the Alcohol Use Disorders Identification Test (AUDIT): WHO Collaborative Project on Early Detection of Persons with Harmful Alcohol Consumption. Addiction. 1993, 88: 791804
Bush, K., Kivlahan, D.R., McDonell, M.S., Fihn, S.D., and Bradley, K.A. The AUDIT Alcohol Consumption Questions (AUDIT-C): an effective brief screening test for problem drinking. Arch Intern Med. 1998, 158: 17891795
Gual, A., Segura, L., Contel, M., Heather, N., and Colom, J. AUDIT-3 and AUDIT-4: effectiveness of two short forms of the alcohol use disorders identification test. Alcohol Alcohol. 2002, 37: 591596
Bourdon, K.H., Rae, D.S., Locke, B.Z., Narrow, W.E., and Regier, D.A. Estimating the prevalence of mental disorders in US. Adults from the Epidemiologic Catchment Area Survey. Public Health Rep. 1992, 107: 663668
Grant, B.F., Hasin, D.S., Chou, S.P., Stinson, F.S., and Dawson, D.A. Nicotine dependence and psychiatric disorders in the United States: results from the national epidemiologic survey on alcohol and related conditions. Arch Gen Psychiatry. 2004, 61: 11071115
Altamirano, J. and Bataller, R. Cigarette smoking and chronic liver diseases. Gut. 2010, 59: 11591162
Fiellin, D.A., OConnor, P.G., Holmboe, E.S., and Horwitz, R.I. Risk for delirium tremens in patients with alcohol withdrawal syndrome. Subst Abuse. 2002, 23: 8394
Amato, L., Minozzi, S., Vecchi, S., and Davoli, M. Benzodiazepines for alcohol withdrawal. Cochrane Database Syst Rev. 2010, 3: CD005063
Mayo-Smith, M.F., Beecher, L.H., Fischer, T.L., Gorelick, D.A., Guillaume, J.L., Hill, A. et al. Management of alcohol withdrawal delirium. An evidence-based practice guideline. Arch Intern Med. 2004, 164: 14051412
McKeon, A., Frye, M.A., and Delanty, N. The alcohol withdrawal syndrome. J Neurol Neurosurg Psychiatry. 2008, 79: 854862
Mayo-Smith, M.F. Pharmacological management of alcohol withdrawal. A meta-analysis and evidence-based practice guideline. American Society of Addiction Medicine Working Group on Pharmacological Management of Alcohol Withdrawal, JAMA. 1997, 278: 144151
Bayard, M., McIntyre, J., Hill, K.R., and Woodside, J. Jr. Alcohol withdrawal syndrome. Am J Fam Physician. 2004, 69: 14431450
Addolorato, G., Leggio, L., Abenavoli, L., Agabio, R., Caputo, F., Capristo, E. et al. Baclofen in the treatment of alcohol withdrawal syndrome: a comparative study versus diazepam. Am J Med. 2006, 119: 1318
Leggio, L., Kenna, G., and Swift, R. New developments for the pharmacological treatment of alcohol withdrawal syndrome. A focus on non-benzodiazepine GABAergic medications. Prog Neuropsychopharmacol Biol Psychiatry. 2008, 32: 11061117
Krampe, H. and Ehrenreich, H. Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Curr Pharm Des. 2010, 16: 20762090
Forns, X., Caballera, J., Bruguera, M., Salmern, J.M., Vilella, A., Mas, A. et al. Disulfiram-induced hepatitis. Report of four cases and review of the literature. J Hepatol. 1994, 21: 853857
Anton, R.F. Naltrexone for the management of alcohol dependence. N Engl J Med. 2008, 359: 715721
Kiefer, F. and Mann, K. Acamprosate: how, where, and for whom does it work? Mechanism of action, treatment targets, and individualized therapy. Curr Pharm Des. 2010, 16: 20982102
Anton, R.F., OMalley, S.S., Ciraulo, D.A., Cisler, R.A., Couper, D., Donovan, D.M. et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA. 2006, 295: 20032017
Garbutt, J.C., Kranzler, H.R., OMalley, S.S., Gastfriend, D.R., Pettinati, H.M., Silverman, B.L. et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA. 2005, 293: 16171625
Rsner, S., Hackl-Herrwerth, A., Leucht, S., Lehert, P., Vecchi, S., and Soyka, M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010, 9: CD004332
Addolorato, G., Leggio, L., Ferrulli, A., Caputo, F., and Gasbarrini, A. The therapeutic potential of gamma-hydroxybutyric acid for alcohol dependence: balancing the risks and benefits. A focus on clinical data. Expert Opin Investig Drugs. 2009, 18: 675686
Heilig, M. and Egli, M. Pharmacological treatment of alcohol dependence: target symptoms and target mechanisms. Pharmacol Ther. 2006, 111: 855876
Johnson, B.A., Rosenthal, N., Capece, J.A., Wiegand, F., Mao, L., Beyers, K. et al. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA. 2007, 298: 16411651
Johnson, B.A., Rosenthal, N., Capece, J.A., Wiegand, F., Mao, L., Beyers, K. et al. Improvement of physical health and quality of life of alcohol-dependent individuals with topiramate treatment: US multisite randomized controlled trial. Arch Intern Med. 2008, 168: 11881199
Johnson, B.A. Medication treatment of different types of alcoholism. Am J Psychiatry. 2010, 167: 630639
Addolorato, G. and Leggio, L. Safety and efficacy of baclofen in the treatment of alcohol dependent patients. Curr Pharm Des. 2010, 16: 21132117
Addolorato, G., Leggio, L., Ferrulli, A., Cardone, S., Vonghia, L., Mirijello, A. et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet. 2007, 370: 19151922
University of Sheffield Guidance Title: Prevention and early identification of alcohol use disorders in adults and young people. Final draft of Report 2 to the National Institute for Health &, Clinical Excellence. Sheffield: The University of Sheffield, School of Health and Related Research (ScHARR), 2009.
Kaner, E.F., Dickinson, H.O., Beyer, F., Pienaar, E., Schlesinger, C., Campbell, F. et al. The effectiveness of brief alcohol interventions in primary care settings: a systematic review. Drug Alcohol Rev. 2009, 28: 301323
Vasilaki, E.I., Hosier, S.G., and Cox, W.M. The efficacy of motivational interviewing as a brief intervention for excessive drinking: a meta-analytic review. Alcohol Alcohol. 2006, 41: 328335
Teli, M.R., Day, C.P., Burt, A.D., Bennett, M.K., and James, O.F. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet. 1995, 346: 987990
Baraona, E. and Lieber, C.S. Alcohol and lipids. in: M. Galanter (Ed.) The consequences of alcoholism. Plenum Press, New York, 1998: 97134
You, M., Considine, R.V., Leone, T.C., Kelly, D.P., and Crabb, D.W. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology. 2005, 42: 568577
Nakajima, T., Kamijo, Y., Tanaka, N., Sugiyama, E., Tanaka, E., Kiyosawa, K. et al. Peroxisome proliferator-activated receptor alpha protects against alcohol-induced liver damage. Hepatology. 2004, 40: 972980
Ji, C., Chan, C., and Kaplowitz, N. Predominant role of sterol response element binding proteins (SREBP) lipogenic pathways in hepatic steatosis in the murine intragastric ethanol feeding model. J Hepatol. 2006, 45: 717724
Chedid, A., Mendenhall, C.L., Gartside, P., French, S.W., Chen, T., and Rabin, L. Prognostic factors in alcoholic liver disease. VA Cooperative Study Group. Am J Gastroenterol. 1991, 86: 210216
Niemela, O., Juvonen, T., and Parkkila, S. Immunohistochemical demonstration of acetaldehyde-modified epitopes in human liver after alcohol consumption. J Clin Invest. 1991, 87: 13671374
Theruvathu, J.A., Jaruga, P., Nath, R.G., Dizdaroglu, M., and Brooks, P.J. Polyamines stimulate the formation of mutagenic 1,N2-propanodeoxyguanosine adducts from acetaldehyde. Nucleic Acids Res. 2005, 33: 35133520
Seitz, H.K. and Stickel, F. Risk factors and mechanisms of hepatocarcinogenesis with special emphasis on alcohol and oxidative stress. Biol Chem. 2006, 387: 349360
Wang, Y., Millonig, G., Nair, J., Patsenker, E., Stickel, F., Mueller, S. et al. Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease. Hepatology. 2009, 50: 453461
Albano, E. Alcohol, oxidative stress and free radical damage. Proc Nutr Soc. 2006, 65: 278290
Lieber, C.S. Cytochrome P-4502E1: its physiological and pathological role. Physiol Rev. 1997, 77: 517544
Dupont, I., Lucas, D., Clot, P., Menez, C., and Albano, E. Cytochrome P4502E1 inducibility and hydroxyethyl radical formation among alcoholics. J Hepatol. 1998, 28: 564571
Seth, D., Gorrell, M.D., Cordoba, S., McCaughan, G.W., and Haber, P.S. Intrahepatic gene expression in human alcoholic hepatitis. J Hepatol. 2006, 45: 306320
Urbaschek, R., McCuskey, R.S., Rudi, V., Becker, K.P., Stickel, F., Urbaschek, B. et al. Endotoxin, endotoxin-neutralizing-capacity, sCD14, sICAM-1, and cytokines in patients with various degrees of alcoholic liver disease. Alcohol Clin Exp Res. 2001, 25: 261268
Thurman, R.G. II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol. 1998, 275: G605G611
Bardag-Gorce, F., Yuan, Q.X., Li, J., French, B.A., Fang, C., Ingelman-Sundberg, M. et al. The effect of ethanol-induced cytochrome p4502E1 on the inhibition of proteasome activity by alcohol. Biochem Biophys Res Commun. 2000, 279: 2329
Bataller, R. and Brenner, D.A. Liver fibrosis. J Clin Invest. 2005, 115: 209218
Cubero, F.J., Urtasun, R., and Nieto, N. Alcohol and liver fibrosis. Semin Liver Dis. 2009, 29: 211221
Moreno, M. and Bataller, R. Cytokines and renin-angiotensin system signaling in hepatic fibrosis. Clin Liver Dis. 2008, 12: 825852
Firrincieli, D., Boissan, M., and Chignard, N. Epithelial-mesenchymal transition in the liver. Gastroenterol Clin Biol. 2010, 34: 523528
Becker, U., Deis, A., Sorensen, T.I., Gronbaek, M., Borch-Johnsen, K., Muller, C.F. et al. Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study. Hepatology. 1996, 23: 10251029
Bellentani, S., Saccoccio, G., Costa, G., Tiribelli, C., Manenti, F., Sodde, M. et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut. 1997, 41: 845850
Becker, U., Gronbaek, M., Johansen, D., and Sorensen, T.I. Lower risk for alcohol-induced cirrhosis in wine drinkers. Hepatology. 2002, 35: 868875
Pelletier, S., Vaucher, E., Aider, R., Martin, S., Perney, P., Balmes, J.L. et al. Wine consumption is not associated with a decreased risk of alcoholic cirrhosis in heavy drinkers. Alcohol Alcohol. 2002, 37: 618621
Barrio, E., Tome, S., Rodriguez, I., Gude, F., Sanchez-Leira, J., Perez-Becerra, E. et al. Liver disease in heavy drinkers with and without alcohol withdrawal syndrome. Alcohol Clin Exp Res. 2004, 28: 131136
Wechsler, H. and Austin, S.B. Binge drinking: the five/four measure. J Stud Alcohol. 1998, 59: 122124
Hatton, J., Burton, A., Nash, H., Munn, E., Burgoyne, L., and Sheron, N. Drinking patterns, dependency and life-time drinking history in alcohol-related liver disease. Addiction. 2009, 104: 587592
Lu, X.L., Luo, J.Y., Tao, M., Gen, Y., Zhao, P., Zhao, H.L. et al. Risk factors for alcoholic liver disease in China. World J Gastroenterol. 2004, 10: 24232426
Corrao, G., Lepore, A.R., Torchio, P., Valenti, M., Galatola, G., DAmicis, A. et al. The effect of drinking coffee and smoking cigarettes on the risk of cirrhosis associated with alcohol consumption. A case-control study. Provincial Group for the Study of Chronic Liver Disease. Eur J Epidemiol. 1994, 10: 657664
Klatsky, A.L., Morton, C., Udaltsova, N., and Friedman, G.D. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med. 2006, 166: 11901195
Tanaka, K., Tokunaga, S., Kono, S., Tokudome, S., Akamatsu, T., Moriyama, T. et al. Coffee consumption and decreased serum gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers. Int J Epidemiol. 1998, 27: 438443
Chronic alcoholic hepatitis symptoms
Loft, S., Olesen, K.L., and Dossing, M. Increased susceptibility to liver disease in relation to alcohol consumption in women. Scand J Gastroenterol. 1987, 22: 12511256
Norton, R., Batey, R., Dwyer, T., and MacMahon, S. Alcohol consumption and the risk of alcohol related cirrhosis in women. Br Med J (Clin Res Ed). 1987, 295: 8082
Pares, A., Caballeria, J., Bruguera, M., Torres, M., and Rodes, J. Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage. J Hepatol. 1986, 2: 3342
Sato, N., Lindros, K.O., Baraona, E., Ikejima, K., Mezey, E., Jarvelainen, H.A. et al. Sex difference in alcohol-related organ injury. Alcohol Clin Exp Res. 2001, 25: 40S45S
Eagon, P.K. Alcoholic liver injury: influence of gender and hormones. World J Gastroenterol. 2010, 16: 13771384
Frezza, M., di Padova, C., Pozzato, G., Terpin, M., Baraona, E., and Lieber, C.S. High blood alcohol levels in women. The role of decreased gastric alcohol dehydrogenase activity and first-pass metabolism. N Engl J Med. 1990, 322: 9599
Mandayam, S., Jamal, M.M., and Morgan, T.R. Epidemiology of alcoholic liver disease. Semin Liver Dis. 2004, 24: 217232
Stewart, S.H. and Connors, G.J. Ethnicity, alcohol drinking and changes in transaminase activity among heavy drinkers. J Natl Med Assoc. 2007, 99: 564569
Wickramasinghe, S.N., Corridan, B., Izaguirre, J., Hasan, R., and Marjot, D.H. Ethnic differences in the biological consequences of alcohol abuse: a comparison between south Asian and European males. Alcohol Alcohol. 1995, 30: 675680
Stinson, F.S., Grant, B.F., and Dufour, M.C. The critical dimension of ethnicity in liver cirrhosis mortality statistics. Alcohol Clin Exp Res. 2001, 25: 11811187
Naveau, S., Giraud, V., Borotto, E., Aubert, A., Capron, F., and Chaput, J.C. Excess weight risk factor for alcoholic liver disease. Hepatology. 1997, 25: 108111
Raynard, B., Balian, A., Fallik, D., Capron, F., Bedossa, P., Chaput, J.C. et al. Risk factors of fibrosis in alcohol-induced liver disease. Hepatology. 2002, 35: 635638
Bellentani, S., Pozzato, G., Saccoccio, G., Crovatto, M., Croce, L.S., Mazzoran, L. et al. Clinical course and risk factors of hepatitis C virus related liver disease in the general population: report from the Dionysos study. Gut. 1999, 44: 874880
Boccato, S., Pistis, R., Noventa, F., Guido, M., Benvegnu, L., and Alberti, A. Fibrosis progression in initially mild chronic hepatitis C. J Viral Hepat. 2006, 13: 297302
Pessione, F., Degos, F., Marcellin, P., Duchatelle, V., Njapoum, C., Martinot-Peignoux, M. et al. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology. 1998, 27: 17171722
Serfaty, L., Chazouilleres, O., Poujol-Robert, A., Morand-Joubert, L., Dubois, C., Chretien, Y. et al. Risk factors for cirrhosis in patients with chronic hepatitis C virus infection: results of a case-control study. Hepatology. 1997, 26: 776779
Wiley, T.E., McCarthy, M., Breidi, L., and Layden, T.J. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998, 28: 805809
Harris, D.R., Gonin, R., Alter, H.J., Wright, E.C., Buskell, Z.J., Hollinger, F.B. et al. The relationship of acute transfusion-associated hepatitis to the development of cirrhosis in the presence of alcohol abuse. Ann Intern Med. 2001, 134: 120124
Machado, M.V., Ravasco, P., Martins, A., Almeida, M.R., Camilo, M.E., and Cortez-Pinto, H. Iron homeostasis and H63D mutations in alcoholics with and without liver disease. World J Gastroenterol. 2009, 15: 106111
Ganne-Carrie, N., Christidis, C., Chastang, C., Ziol, M., Chapel, F., Imbert-Bismut, F. et al. Liver iron is predictive of death in alcoholic cirrhosis: a multivariate study of 229 consecutive patients with alcoholic and/or hepatitis C virus cirrhosis: a prospective follow-up study. Gut. 2000, 46: 277282
Ropero Gradilla, P., Villegas Martinez, A., Fernandez Arquero, M., Garcia-Agundez, J.A., Gonzalez Fernandez, F.A., Benitez Rodriguez, J. et al. C282Y and H63D mutations of HFE gene in patients with advanced alcoholic liver disease. Rev Esp Enferm Dig. 2001, 93: 156163
Hrubec, Z. and Omenn, G.S. 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. 1981, 5: 207215
Reed, T., Page, W.F., Viken, R.J., and Christian, J.C. Genetic predisposition to organ-specific end points of alcoholism. Alcohol Clin Exp Res. 1996, 20: 15281533
Zintzaras, E., Stefanidis, I., Santos, M., and Vidal, F. Do alcohol-metabolizing enzyme gene polymorphisms increase the risk of alcoholism and alcoholic liver disease?. Hepatology. 2006, 43: 352361
Stickel, F. and Osterreicher, C.H. The role of genetic polymorphisms in alcoholic liver disease. Alcohol Alcohol. 2006, 41: 209224
Tian, C., Stokowski, R.P., Kershenobich, D., Ballinger, D.G., and Hinds, D.A. Variant in PNPLA3 is associated with alcoholic liver disease. Nat Genet. 2010, 42: 2123
Stickel, F., Buch, S., Lau, K., Meyer zu Schwabedissen, H., Berg, T., Ridinger, M. et al. Genetic variation in the PNPLA3 gene is associated with alcoholic liver injury in caucasians. Hepatology. 2010, 53: 8695
MacSween, R.N. and Burt, A.D. Histologic spectrum of alcoholic liver disease. Semin Liver Dis. 1986, 6: 221232
Lefkowitch, J.H. Morphology of alcoholic liver disease. Clin Liver Dis. 2005, 9: 3753
Hall, P.D. Pathological spectrum of alcoholic liver disease. Alcohol Alcohol. 1994, 2: 303313
Edmondson, H.A., Peters, R.L., Frankel, H.H., and Borowsky, S. The early stage of liver injury in the alcoholic. Medicine (Baltimore). 1967, 46: 119129
Telli, M.R., Day, C.P., Burt, A.D., Bennett, M.K., and James, O.F. Determinants of progression to cirrhosis or fibrosis in pure alcoholic fatty liver. Lancet. 1995, 346: 987990
Galambos, J.T. and Shapira, R. Natural history of alcoholic hepatitis. J Clin Invest. 1973, 52: 29522962
Marbet, U.A., Bianchi, L., Meury, U., and Stalder, G.A. Long-term histological evaluation of the natural history and prognostic factors of alcoholic liver disease. J Hepatol. 1987, 4: 364372
Nakano, M., Worner, T.M., and Lieber, C.S. Perivenular fibrosis in alcoholic liver injury: ultrastructure and histologic progression. Gastroenterology. 1982, 83: 777785
Worner, T.M. and Lieber, C.S. Perivenular fibrosis as precursor lesion of cirrhosis. JAMA. 1985, 254: 627630
Galambos, J.T. Natural history of alcoholic hepatitis. Gastroenterology. 1972, 63: 10261035
Sorensen, T.I., Orholm, M., Bentsen, K.D., Hoybye, G., Eghoje, K., and Christoffersen, P. Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet. 1984, 2: 241244
Mathurin, P., Beuzin, F., Louvet, A., Carrie-Ganne, N., Balian, A., Trinchet, J.C. et al. Fibrosis progression occurs in a subgroup of heavy drinkers with typical histological features. Aliment Pharmacol Ther. 2007, 25: 10471054