Alcoholic Liver Disease Research:
2002-2006
  
J Clin Gastroenterol. 2006 Oct;40(9):833-841.
Acute Alcoholic Hepatitis.
Ceccanti M, Attili A, Balducci G, Attilia F, Giacomelli S, Rotondo C, Sasso GF, Xirouchakis E, Attilia ML.
*Alcohol Liver Disease Unit daggerII Gastroenterology Unit, University "La Sapienza", Roma, Italy double daggerIstituto Superiore di Sanita, Roma, Italy section sign1st IKA Hospital Gastroenterology Unit, Athens, Greece.

Acute alcoholic hepatitis (AAH) is a frequent inflammatory liver disease with high short-term mortality rate. In this review, relationships between alcohol abuse and the epidemiology and the outcomes of AAH are discussed, as well as AAH pathogenesis. The role of endotoxins, tumor necrosis factor alpha, fibroblasts, and immune response to altered hepatocyte proteins is discussed. The need of a careful prognosis, supported by the use of Maddrey score, by the model for end-stage liver disease [Mayo end-stage liver disease (MELD)] score or by the Glasgow alcoholic hepatitis score, is outlined, as the use of the most effective drugs (glucocorticoids and anti-tumor necrosis factor alpha infliximab) is recommended only in severe AAH cases. The problems of liver transplant in severe AAH, and the need of a 6-month alcohol abstinence before transplant, are discussed, as well as the need of a careful psychologic assessment before the transplant.

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Aliment Pharmacol Ther. 2006 Oct 15;24(8):1151-61.
Review article: alcoholic liver disease--pathophysiological aspects and risk factors.
Gramenzi A, Caputo F, Biselli M, Kuria F, Loggi E, Andreone P, Bernardi M.
Dipartimento di Medicina Interna, Cardioangiologia ed Epatologia, Universita di Bologna, Policlinico S. Orsola, Via Massarenti 9, 40138 Bologna, Italy.

BACKGROUND: Alcoholic liver disease has a known aetiology but a complex and incompletely known pathogenesis. It is an extremely common disease with significant morbidity and mortality, but the reason why only a relatively small proportion of heavy drinkers progress to advanced disease remains elusive. AIM: To recognize the factors responsible for the development and progression of alcoholic liver disease, in the light of current knowledge on this matter. METHODS: We performed a structured literature review identifying studies focusing on the complex pathogenetic pathway and risk factors of alcoholic liver disease. Results In addition to the cumulative amount of alcohol intake and alcohol consumption patterns, factors such as gender and ethnicity, genetic background, nutritional factors, energy metabolism abnormalities, oxidative stress, immunological mechanisms and hepatic co-morbid conditions play a key role in the genesis and progression of alcoholic liver injury. CONCLUSIONS: Understanding the pathogenesis and risk factors of alcoholic liver disease should provide insight into the development of therapeutic strategies.

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Br J Anaesth. 2006 Oct;97(4):496-8. Epub 2006 Jul 18.
One year outcome of intensive care patients with decompensated alcoholic liver disease.
Mackle IJ, Swann DG, Cook B.
Department of Anaesthesia, Critical Care and Pain Management, The Royal Infirmary of Edinburgh at Little France 51 Little France Crescent, Old Dalkeith Road, Edinburgh EH16 4SA, UK.

BACKGROUND: We aimed to examine the outcome of patients with decompensated alcoholic liver disease (ALD) admitted to a general intensive care unit (ICU). METHODS: Retrospective observational cohort study of intensive care admissions over a 3 yr period was conducted. The study was set in an ICU in a UK university hospital with a tertiary liver referral unit. One hundred and ten admissions, involving 107 patients, with decompensated ALD were included. Intensive care, hospital, and 6 and 12 months mortality were recorded along with the outcome in diagnostic and organ system support subgroups. Intensive care, hospital, 6 month and 12 month mortality rates were 58, 71, 78 and 81%. RESULTS: Hospital mortality in the sepsis/multiorgan failure group was 88%. Sixty-nine per cent of patients who were ventilated but required no other organ support survived to hospital discharge. However, the requirement for any other organ support, or a raised creatinine (>120 mumol litre(-1)) in the first 24 h, reduced the hospital survival to <15%. In those patients requiring acute renal replacement therapy, the hospital mortality was 94%. CONCLUSION: Decompensated ALD requiring intensive care admission is associated with a high hospital mortality and consideration should be given to the futility of escalating organ support measures, particularly when renal replacement therapy is required.

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Rev Med Suisse. 2006 Sep 6;2(77):1974-8.
[Clinical management of a patient with alcoholic cirrhosis]
[Article in French]
Nguyen-Trang T, Hadengue A, Spahr L.
Service de gastroenterologie et d'hepatologie, HUG, 1211 Geneve 14.

Prolonged abstinence from alcohol is crucial in the management and prognosis of a patient with alcoholic cirrhosis. It is also important to prevent complications such as variceal bleeding, hepatocellular and extrahepatic cancers, and malnutrition. Liver transplantation should be considered in patients with persistent liver failure in spite of complete cessation of alcohol consumption. We provide some recommendations in commonly encountered clinical situations for compensated and decompensated alcoholic cirrhosis.

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Methods Mol Biol. 2006;333:29-46.
Current status of liver transplantation.
Friend PJ, Imber CJ.
Nuffield Department of Surgery, John Radcliffe Hospital, Oxfordshire, Oxford, England.

Liver transplantation has become the treatment of choice for a wide range of end-stage liver disease. As outcomes have improved, so the demand for this therapy has increasingly exceeded the availability of donor organs. Access to liver transplantation is controlled such that donor organs are generally allocated to the patients who are likely to benefit most, although if all patients who might benefit were placed on the waiting list, the donor shortage would be greatly increased. Recurrence of the original liver disease is emerging as an important issue. Fewer patients are transplanted for liver tumors, as earlier results showed a very high rate of recurrence. In recent years there has been a change in the underlying conditions of patients on the waiting list, and a preponderance of patients now present with hepatitis C and alcoholic cirrhosis. Increasingly, transplant units are looking to sources of donor organs that would previously have been deemed unsuitable--such marginal donors include non-heart-beating donors (NHBDs). Results from controlled NHBDs--those cases in which cardiac arrest is predicted--suggest that this is a good source of viable organs. Splitting a donor liver to provide two grafts has successfully enabled the transplantation of a child and an adult from one organ. The transplantation of two adults from a single organ remains a greater challenge. Transplantation from living donors has been practiced increasingly over the last decade, although anxieties have been expressed over donor safety. In many countries this now represents a significant contribution to overall liver transplant activity.

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Hepatology. 2006 Sep;44(3):521-6.
Global challenges in liver disease.
Williams R.
UCL Institute of Hepatology, Division of Medicine, Royal Free and University College Medical School, London, UK. roger.williams@ucl.ac.uk

Immigration, cheap air travel, and globalization are all factors contributing to a worldwide spread of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. End-stage chronic liver disease (ESLD) as a result of co-infection with HBV/HCV is now the major cause of death for individuals who have been infected with the HIV virus. The high incidence of HCV infection in Egypt--the legacy left from the mass use of tartar emetic to eradicate schistosomiasis, as in other high prevalence areas--will take years to reduce. Steatohepatitis due to non-alcoholic fatty liver disease is developing into a new and major health problem as a result of rising levels of obesity in populations worldwide. Hepatic steatosis also has an adverse influence on the progression of other liver diseases including chronic HCV infection and alcoholic liver disease. In many countries, considerable public concern is on the rise due to increased levels of alcohol consumption adversely affecting younger and affluent age groups. With the rising prevalence of cirrhosis, primary hepatocellular carcinoma (HCC) is increasing in frequency as is that of primary intrahepatic cholangiocarcinoma. Finally, despite the successes of liver transplantation, many deserving patients are not getting transplants due to low levels of cadaver organ donation in many countries, thereby increasing pressures on the use of living donor liver transplantation. Only through a concerted effort from governments, health agencies, healthcare professionals at all levels, and the pharmaceutical industry can this grim outlook for liver disease worldwide be reversed.

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Alcohol Alcohol. 2006 Jul-Aug;41(4):358-63. Epub 2006 Apr 24.
Liver transplantation for alcoholic liver disease: a systematic review of psychosocial selection criteria.
McCallum S, Masterton G.
Department of Psychiatry, Queen Margaret Hospital, Whitefield Road, Dunfermline, Fife KY12 0RG, Scotland. seonaid.mccallum@faht.scot.nhs.uk

AIMS: To examine the evidence base for psychosocial selection criteria for liver transplant candidates with alcoholic liver disease. METHOD: Systematic review using three electronic databases supplemented by hand searches. RESULTS: Out of 96 published studies, 22 were included. All but one were cohort design, most were retrospective, single centre, and small sample. Methodology varied considerably, such that meta-analysis was not feasible. CONCLUSIONS: Social stability, no close relatives with an alcohol problem, older age, no repeated alcohol-treatment failures, good compliance with medical care, no current polydrug misuse, and no co-existing severe mental disorder have all been associated with future abstinence in more studies than not, in those that examined these variables. Duration of preoperative abstinence was a poor predictor. We recommend that, if predicting future abstinence is considered necessary by transplant teams, a standardized approach is agreed and deployed amongst transplant units, then audited and reviewed.

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Nutr Clin Pract. 2006 Jun;21(3):245-54.
Nutrition in alcoholic liver disease.
DiCecco SR, Francisco-Ziller N.
William J. von Liebig Transplant Center, Mayo Clinic Rochester, 201 W. Center Street, Rochester, MN 55902, USA. dicecco.sara@mayo.edu

Liver disease secondary to alcohol ranges from alcoholic fatty liver disease to acute hepatitis to cirrhotic liver disease. It is imperative that alcohol be discontinued to allow for any potential improvement in liver function, with most benefit being seen in the early stages of the disease. Alcoholic liver disease has a profound effect on nutrient intake, nutrition status, and metabolism, contributing to a high prevalence of malnutrition in this population. Early intervention with nutrition therapy may improve response to treatment, alleviate symptoms, and improve quality and quantity of life. In this review, nutrition assessment parameters and medical nutrition therapy goals for alcoholic liver disease are discussed.

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Am J Gastroenterol. 2006 Jun;101(6):1370-8. Erratum in: Am J Gastroenterol. 2006 Aug;101(8):1944.
Recurrence of diseases following orthotopic liver transplantation.
Kotlyar DS, Campbell MS, Reddy KR.
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Long-term graft survival and mortality after liver transplantation continue to improve. However, disease recurrence remains a major stumbling block, especially among patients with hepatitis C. Chronic hepatitis C recurs to varying degrees in nearly all patients who undergo transplantation. Transplantation for hepatitis C is associated with higher rates of graft failure and death compared with transplantation for other indications, and retransplantation for hepatitis C related liver failure remains controversial. Recurrence of hepatitis B has been markedly reduced with improved prophylactic regimens. Further, rates of hepatocellular carcinoma recurrence have also decreased, as improved patient selection criteria have prioritized transplantation for those with a low risk of recurrence. Primary biliary cirrhosis recurs in some patients, but it is often relatively mild. Autoimmune liver disease has also been shown to have a relatively benign post-transplantation course, but some studies have indicated that it slowly progresses in most recipients. It has been recently reported that alcoholic liver disease liver transplant recipients who return to drinking have worsened mortality. In such patients worse outcomes are not due to graft failure, but instead to other comorbidities. Recurrences of other diseases, including nonalcoholic steatohepatitis and primary sclerosing cholangitis, are now being recognized as having potentially detrimental effects on graft survival and mortality. Expert clinical management may help prevent and treat complications associated with disease recurrence.

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Alcohol. 2006 May-Jun;41(3):278-83. Epub 2006 Feb 13.
Predictors of relapse to harmful alcohol after orthotopic liver transplantation.
Kelly M, Chick J, Gribble R, Gleeson M, Holton M, Winstanley J, McCaughan GW, Haber PS.
Drug Health Services, Royal Prince Alfred Hospital, Missenden Road, Camperdown, NSW 2050, Australia. phaber@mail.usyd.edu.au.

BACKGROUND: End-stage alcoholic liver disease (ALD) is a common indication for liver transplantation. Outcomes may be limited by return to harmful drinking. Previous studies have identified few predictors of drinking relapse. AIM: This study examined novel postulated predictors of relapse to drinking. METHOD: The case notes of all patients transplanted for ALD at the Royal Prince Alfred Hospital from 1987-2004 were reviewed. Pre-transplant characteristics were rated by a psychiatrist independent of the transplant team, blind to the outcome. Outcomes were rated by a second independent alcohol treatment specialist also blind to the pre-transplant ratings. RESULTS: Of 100 patients, 6 died before discharge from hospital, 4 had <6 months follow-up, 18 relapsed to harmful drinking, 10 drank below harmful levels, and 62 remained abstinent after a mean of 5.6 years follow-up. Univariate analyses identified six potential pre-transplant predictors of return to harmful drinking. These were a diagnosis of mental illness (of which all cases were of depression), the lack of a stable partner, grams per day consumed in the years before assessment for transplant, reliance on 'family or friends' for post-transplant support, tobacco consumption at time of assessment, and lack of insight into the alcohol aetiology. Duration of pre-transplant abstinence and social class by occupation did not predict relapse. A multivariate model based on the above characteristics correctly predicted 89% of the outcomes. CONCLUSION: A model based on readily defined behaviours and psychosocial factors predicted relapse to harmful drinking after transplant for ALD. This model may improve assessment and post-transplant management of patients with advanced ALD.

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Curr Opin Gastroenterol. 2006 May;22(3):263-71.
Alcohol and the liver.
Reuben A.
Liver Service, Division of Gastroenterology/Hepatology and Liver Transplant Program, Medical University of South Carolina, Charleston, 29425, USA. reubena@musc.edu

PURPOSE OF REVIEW: To apprise the reader of advances in 2005 in the epidemiology, pathogenesis, prognosis and treatment of alcoholic liver disease. Alcohol use has declined in developed countries, but the opposite is true elsewhere; alcoholic liver disease is a considerable burden worldwide. RECENT FINDINGS: Genetic mechanisms for alcoholic liver disease are being discovered in addition to aggravating cofactors, such as hepatitis C, obesity and iron overload, and ameliorating ones, like coffee and tea drinking. The involvement of the innate immune system and the mechanisms of apoptosis in alcoholic liver disease are better appreciated, especially the emerging role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Steroid use and nutrition for alcoholic hepatitis are being refined, and the validity of the model for end-stage liver disease (MELD) score in predicting the outcome of alcoholic liver disease is upheld. Recidivism after liver transplantation for alcoholic liver disease adversely impacts long-term survival. SUMMARY: Inroads are being made into the genetics of alcoholic liver disease and new phenomena are being uncovered in its pathogenesis, but safe and effective therapies for both alcoholic hepatitis and alcoholic cirrhosis are still wanting.

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Alcohol Alcohol. 2006 Apr 24; [Epub ahead of print]
Liver transplantation for alcoholic liver disease: a systematic review of psychosocial selection criteria.
McCallum S, Masterton G.
Department of Psychiatry, Queen Margaret Hospital, Fife, Scotland.

AIMS: To examine the evidence base for psychosocial selection criteria for liver transplant candidates with alcoholic liver disease. METHOD: Systematic review using three electronic databases supplemented by hand searches. RESULTS: Out of 96 published studies, 22 were included. All but one were cohort design, most were retrospective, single centre, and small sample. Methodology varied considerably, such that meta-analysis was not feasible. CONCLUSIONS: Social stability, no close relatives with an alcohol problem, older age, no repeated alcohol-treatment failures, good compliance with medical care, no current polydrug misuse, and no co-existing severe mental disorder have all been associated with future abstinence in more studies than not, in those that examined these variables. Duration of preoperative abstinence was a poor predictor. We recommend that, if predicting future abstinence is considered necessary by transplant teams, a standardized approach is agreed and deployed amongst transplant units, then audited and reviewed.

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Cochrane Database Syst Rev. 2006 Apr 19;(2):CD002235.
S-adenosyl-L-methionine for alcoholic liver diseases.
Rambaldi A, Gluud C.

BACKGROUND: Alcohol is a major cause of liver disease and disrupts methionine and oxidative balances. S-adenosyl-L-methionine (SAMe) acts as a methyl donor for methylation reactions and participates in the synthesis of glutathione, the main cellular antioxidant. Randomised clinical trials have addressed the question whether SAMe may benefit patients with alcoholic liver diseases. OBJECTIVES: To evaluate the beneficial and harmful effects of SAMe for patients with alcoholic liver diseases. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (1980 to May 2005), and Science Citation Index Expanded (searched May 2005). SELECTION CRITERIA: We included randomised clinical trials studying patients with alcoholic liver diseases. Interventions encompassed per oral or parenteral administration of SAMe at any dose versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: We performed all analyses according to the intention-to-treat method using RevMan Analyses provided by the Cochrane Collaboration. We evaluated the methodological quality of the randomised clinical trials by quality components. MAIN RESULTS: We identified nine randomised clinical trials including a heterogeneous sample of 434 patients with alcoholic liver diseases. The methodological quality regarding randomisation was generally low, but 8 out of 9 trials were placebo controlled. Only one trial including 123 patients with alcoholic cirrhosis used adequate methodology and reported clearly on all-cause mortality and liver transplantation. We found no significant effects of SAMe on all-cause mortality (relative risks (RR) 0.62, 95% confidence interval (CI) 0.30 to 1.26), liver-related mortality (RR 0.68, 95% CI 0.31 to 1.48), all-cause mortality or liver transplantation (RR 0.55; 95% CI 0.27 to 1.09), or complications (RR 1.35, 95% CI 0.84 to 2.16), but the analysis is based mostly on one trial only. SAMe was not significantly associated with non-serious adverse events (RR 4.92; 95% CI 0.59 to 40.89) and no serious adverse events were reported. AUTHORS' CONCLUSIONS: We could not find evidence supporting or refuting the use of SAMe for patients with alcoholic liver diseases. We need more long-term, high-quality randomised trials on SAMe for these patients before SAMe may be recommended for clinical practice.

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Curr Opin Crit Care. 2006 Apr;12(2):171-7.
The management of severe alcoholic liver disease and variceal bleeding in the intensive care unit.
Berry PA, Wendon JA.
Institute of Liver Studies, Kings College Hospital, London, UK.

PURPOSE OF REVIEW: To address recent advances in the understanding and management of alcohol-related chronic liver disease and its acute complications. RECENT FINDINGS: Refinements have been made in the prognosis and treatment of alcoholic hepatitis, and new insights have been gained into the pathophysiology of the hepatorenal syndrome. Further trial evidence has emerged concerning therapy in the hepatorenal syndrome, and there has been some clarification of the benefits and risks relating to albumin dialysis/extracorporeal liver support, and consensus in the early management of variceal haemorrhage. SUMMARY: Recent developments have led to modifications in the standard of care of patients with severe alcoholic liver disease, many of which are highly applicable to the general critical care setting. These changes apply specifically to alcoholic hepatitis, the hepatorenal syndrome and variceal bleeding, common conditions with a high mortality rate, upon which changes in practice can have a significant impact.

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Dig Dis. 2005;23(3-4):275-84.
Treatment of alcoholic liver disease.
Bergheim I, McClain CJ, Arteel GE.
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.

Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60% (worse than many common cancers such as breast and prostate). The cornerstone for therapy for ALD is lifestyle modification, including drinking cessation and treatment of decompensation, if appropriate. Nutrition intervention has been shown to play a positive role on both an in-patient and out-patient basis. Corticosteroids are effective in selected patients with alcoholic hepatitis, and treatment with pentoxifylline appears to be a promising anti-inflammatory therapy. Recent studies have indicated anti-TNFalpha therapy, at least for alcoholic hepatitis. Some complementary and alternative medicinal agents, such as milk thistle and S-adenosylmethionine, may be effective in alcoholic cirrhosis. Treatment of the complications of ALD can improve the quality of life and, in some cases, decrease short-term mortality. Copyright 2005 S. Karger AG, Basel.

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Alcohol Clin Exp Res. 2005 Dec;29(12 Suppl):259S-63S.
Difference and similarity between non-alcoholic steatohepatitis and alcoholic liver disease.
Kojima H, Sakurai S, Uemura M, Takekawa T, Morimoto H, Tamagawa Y, Fukui H.
Third Department of Internal Medicine, Nara Medical University, Japan. kojima@nmu.gw.naramed-u.ac.jp

BACKGROUND: Non-alcoholic steatohepatitis (NASH) and alcoholic liver disease (ALD) are extremely similar in the pathologic findings and pathogenesis. This study aimed to elucidate the difference and similarity between these diseases. METHODS: Twenty-six patients with NASH and 26 with ALD including 11 with alcoholic hepatitis underwent clinico-pathologic analysis. The visceral fat area and liver/spleen ratio, an index of the hepatic fat content, were evaluated with computed tomography. The hepatic iron deposit and oxidative stress induced-lipid peroxidation were estimated by Prussian blue staining and 3-nitrotyrosine staining, respectively. RESULTS: The most prominent difference between NASH and ALD was the nutritional status, although elevation of AST/ALT ratio and gamma-GT is relatively characteristic of ALD. NASH was more frequently associated with diabetes mellitus as compared with ALD. The BMI and serum levels of total cholesterol and cholinesterase were higher in NASH than in ALD. Although the degree and distribution of fibrosis and necro-inflammatory reaction were similar in NASH and ALD, steatosis was more severe in NASH than in ALD. The liver/spleen ratio was lower and the visceral fat area was larger in NASH than in ALD, regardless of the coincidence of alcoholic hepatitis. Interestingly, the visceral fat area positively correlated with ALT and HOMA-IR in NASH, whereas these correlations were not observed in ALD. The hepatic iron deposit was less in NASH than in ALD, whereas lipid peroxidation in NASH was similar to that in ALD with alcoholic hepatitis and more advanced as compared with that in ALD without alcoholic hepatitis. CONCLUSIONS: NASH was characterized with over-nutrition and visceral fat type obesity as compared with ALD. The visceral fat accumulation was associated with hepatic inflammation and insulin resistance in NASH, but not in ALD. The difference in the nutritional status between NASH and ALD is not only reflected in the clinical features but also may closely associate with the mechanisms of hepatocellular damage in these diseases.

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Alcohol Clin Exp Res. 2005 Nov;29(11 Suppl):162S-5S.
Glycine as a therapeutic immuno-nutrient for alcoholic liver disease.
Yamashina S, Ikejima K, Enomoto N, Takei Y, Sato N.
>From the Department of Gastroenterology (SY, KI, NE, YT, NS), Juntendo University School of Medicine, Tokyo, Japan.

Activation of Kupffer cells by gut-derived endotoxin is an important factor in ethanol hepatotoxicity. Further, it was shown that ethanol modulates both the expression and activity of several intracellular signaling molecules and transcription factors in Kupffer cells and chronic ethanol treatment enhances Kupffer cell sensitivity to endotoxin. These findings suggest that inhibition of Kupffer cell activation is effective for clinical application in alcoholic hepatitis. Recently, accumulating lines of evidence suggest a possibility that glycine is useful as an immuno-modulating amino acid. It has been shown that a diet containing glycine improved survival in endotoxin shock by preventing Kupffer cell activation. Glycine most likely prevents the LPS-induced elevation of intracellular Ca concentration in Kupffer cells, thereby minimizing LPS receptor signaling and cytokine production. Indeed, glycine prevents alcohol-induced liver injury in a long-term enteral ethanol feeding rats (Tsukamoto-French) by decreasing production of TNF-alpha in the liver. Moreover, glycine is protective against apoptosis of sinusoidal endothelial cells (SECs) that is one of the initial events in the development of liver injury. On the other hand, epidemiologic data have identified chronic alcohol consumption as a significant risk factor for carcinogenesis. Interestingly, glycine inhibits growth of tumor in vivo most likely because of the inhibition of angiogenesis. It was shown that the inhibitory effect of glycine on growth and migration of endothelial cells is due to activation of a glycine-gated Cl channel. It is hypothesized that the opening of this anion channel hyperpolarizes the cell membrane, blocks influx of Ca through voltage-dependent Ca channel, thereby blunting growth factor-mediated signaling. Therefore, glycine can be used not only for treatment of alcoholic hepatitis, but also for chemoprevention and treatment of hepatocellular carcinoma in alcoholic cirrhosis. Taken together, it is concluded that glycine is a potent therapeutic immuno-nutrient for various kinds of chronic liver diseases including alcoholic liver disease (ALD).

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Am J Gastroenterol. 2005 Nov;100(11):2583-91.
Milk thistle for alcoholic and/or hepatitis B or C liver diseases--a systematic cochrane hepato-biliary group review with meta-analyses of randomized clinical trials.
Rambaldi A, Jacobs BP, Iaquinto G, Gluud C.
Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark.

OBJECTIVES: Our objectives were to assess the beneficial and harmful effects of milk thistle (MT) or MT constituents versus placebo or no intervention in patients with alcoholic liver disease and/or hepatitis B and/or C liver diseases. METHODS: Randomized clinical trials studying patients with alcoholic and/or hepatitis B or C liver diseases were included (December 2003). The randomized clinical trials were evaluated by components of methodological quality. RESULTS: Thirteen randomized clinical trials assessed MT in 915 patients with alcoholic and/or hepatitis B or C liver diseases. The methodological quality was low: only 23% of the trials reported adequate allocation concealment and only 46% were considered double blind. MT versus placebo or no intervention for a median duration of 6 months had no significant effects on all-cause mortality (relative risk (RR) 0.78, 95% confidence interval (CI) 0.53-1.15), complications of liver disease, or liver histology. Liver-related mortality was significantly reduced by MT in all trials (RR 0.50, 95% CI 0.29-0.88), but not in high-quality trials (RR 0.57, 95% CI 0.28-1.19). MT was not associated with a significantly increased risk of adverse events. CONCLUSIONS: Based on high-quality trials, MT does not seem to significantly influence the course of patients with alcoholic and/or hepatitis B or C liver diseases. MT could potentially affect liver injury. Adequately conducted randomized clinical trials on MT versus placebo may be needed.

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Liver Transpl. 2005 Nov;11(11 Suppl 2):S21-4.
Is alcoholic hepatitis an indication for transplantation? Current management and outcomes.
Mathurin P.
Service d'Hepatogastroenterologie Hopital Claude Huriez and Equipe mixte INSERM 0114, CHU Lille, France. p-mathurin@chrulille.fr

1. In the absence of treatment, 50% of patients with severe alcoholic hepatitis (AH) [Maddrey function (DF) >or= 32] die 2 months later. Among patients with severe AH treated by corticosteroids, 80% had 2-month survival. Pentoxifylline is considered by some investigators to be an alternative option to corticosteroids. 2. Non-responders to corticosteroids (NRCs) have poor survival and require new strategies. Liver transplantation should be considered in order to improve survival of non-responders to therapeutic agents. 3. Prognostic models such as the Model for End-Stage Liver Disease (MELD) and DF are useful tools for predicting short-term mortality of patients with severe AH. Specific models taking into account the particular settings of treated patients are warranted. 4. In an era of organ shortage, use of liver transplants in patients with severe AH may negatively affect the public attitude on transplantation and organ donation, and may cause reluctance on the part of clinicians to modify guidelines for alcoholic patients. 5. Therefore, a reasonable approach would be to carry out only pilot studies on only a small cohort of patients to determine whether transplantation improves survival in patients with severe AH.

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Rocz Akad Med Bialymst. 2005;50:7-20.
Pathogenesis and treatment of alcoholic liver disease: progress over the last 50 years.
Lieber CS.
Alcohol Research and Treatment Center, Section of Liver Disease and Nutrition, Bronx VA Medical Center, New York 10468, USA. liebercs@aol.com

Fifty years ago the dogma prevailed that alcohol was not toxic to the liver and that alcoholic liver disease was exclusively a consequence of nutritional deficiencies. We showed, however, that liver pathology developed even in the absence of malnutrition. This toxicity of alcohol was linked to its metabolism via alcohol dehydrogenase which converts nicotinamide adenine dinucleotide (NAD) to nicotinamide adenine dinucleotide-reduced form (NADH) which contributes to hyperuricemia, hypoglycemia and hepatic steatosis by inhibiting lipid oxidation and promoting lipogenesis. We also discovered a new pathway of ethanol metabolism, the microsomal ethanol oxidizing system (MEOS). The activity of its main enzyme, cytochrome P4502E1 (CYP2E1), and its gene are increased by chronic consumption, resulting in metabolic tolerance to ethanol. CYP2E1 also detoxifies many drugs but occasionally toxic and even carcinogenic metabolites are produced. This activity is also associated with the generation of free radicals with resulting lipid peroxidation and membrane damage as well as depletion of mitochondrial reduced glutathione (GSH) and its ultimate precursor, namely methionine activated to S-adenosylmethionine (SAMe). Its repletion restores liver functions. Administration of polyenylphosphatidylcholine (PPC), a mixture of unsaturated phosphatidylcholines (PC) extracted from soybeans, restores the structure of the membranes and the function of the corresponding enzymes. Ethanol impairs the conversion of beta-carotene to vitamin A and depletes hepatic vitamin A and, when it is given together with vitamin A or beta-carotene, hepatotoxicity is potentiated. Our present therapeutic approach is to reduce excess alcohol consumption by the Brief Intervention technique found to be very successful. We correct hepatic SAMe depletion and supplementation with PPC has some favorable effects on parameters of liver damage which continue to be evaluated. Similarly dilinoleoylphosphatidylcholine (DLPC), PPC's main component, also partially opposes the increase in CYP2E1 by ethanol. Hence, therapy with SAMe +DLPC is now being considered.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002800.
Propylthiouracil for alcoholic liver disease.
Rambaldi A, Gluud C, Rambaldi A.

BACKGROUND: Randomised clinical trials have addressed the question whether propylthiouracil has any beneficial effects in patients with alcoholic liver disease. OBJECTIVES: To assess the beneficial and harmful of propylthiouracil for patients with alcoholic liver disease. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (1980 to May 2005), and The Web of Science (May 2005) were searched. These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included irrespective of blinding, publication status, or language. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method in RevMan Analyses. The methodological quality of the randomised clinical trials was evaluated by components (generation of the allocation sequence; allocation concealment; double blinding; follow-up). MAIN RESULTS: Combining the results of six randomised clinical trials including 710 patients demonstrated no significant effects of propylthiouracil versus placebo on all-cause mortality (relative risks (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30), liver-related mortality (RR 0.80, 95% CI 0.50 to 1.29), complications of the liver disease, or liver histology. Propylthiouracil was associated with a non-significant increased risk of non-serious adverse events and with the seldom occurrence of serious adverse events (leukopenia). AUTHORS' CONCLUSIONS: We could not demonstrate any significant beneficial effect of propylthiouracil on all-cause mortality, liver-related mortality, liver complications, and liver histology of patients with alcoholic liver disease. Propylthiouracil was associated with adverse events. Confidence intervals were wide. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.

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Cochrane Database Syst Rev. 2005 Oct 19;(4):CD002800.
Propylthiouracil for alcoholic liver disease.
Rambaldi A, Gluud C, Rambaldi A.

BACKGROUND: Randomised clinical trials have addressed the question whether propylthiouracil has any beneficial effects in patients with alcoholic liver disease. OBJECTIVES: To assess the beneficial and harmful of propylthiouracil for patients with alcoholic liver disease. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register (May 2005), The Cochrane Central Register of Controlled Trials in The Cochrane Library (Issue 2, 2005), MEDLINE (1950 to May 2005), EMBASE (1980 to May 2005), and The Web of Science (May 2005) were searched. These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included irrespective of blinding, publication status, or language. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method in RevMan Analyses. The methodological quality of the randomised clinical trials was evaluated by components (generation of the allocation sequence; allocation concealment; double blinding; follow-up). MAIN RESULTS: Combining the results of six randomised clinical trials including 710 patients demonstrated no significant effects of propylthiouracil versus placebo on all-cause mortality (relative risks (RR) 0.93, 95% confidence interval (CI) 0.66 to 1.30), liver-related mortality (RR 0.80, 95% CI 0.50 to 1.29), complications of the liver disease, or liver histology. Propylthiouracil was associated with a non-significant increased risk of non-serious adverse events and with the seldom occurrence of serious adverse events (leukopenia). AUTHORS' CONCLUSIONS: We could not demonstrate any significant beneficial effect of propylthiouracil on all-cause mortality, liver-related mortality, liver complications, and liver histology of patients with alcoholic liver disease. Propylthiouracil was associated with adverse events. Confidence intervals were wide. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.

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Curr Med Res Opin. 2005 Sep;21(9):1337-46.
Alcoholic hepatitis: from pathogenesis to treatment.
Sougioultzis S, Dalakas E, Hayes PC, Plevris JN.
Department of Hepatology, The Royal Infirmary of Edinburgh and University of Edinburgh, UK.

Alcoholic hepatitis is a serious complication of alcohol abuse due to its high mortality rates particularly at short term. It may complicate pre-existing alcoholic fatty liver or cirrhosis and is mainly diagnosed on clinical and laboratory grounds although liver biopsy is occasionally needed to exclude other pathology and confirm the diagnosis. Accumulating evidence suggests that cytokines and immunity are actively involved in its pathogenesis. Management includes abstinence and supportive care. Treatment with corticosteroids has been studied in several clinical trials with conflicting results. However, recent evidence supporting the beneficial effect of TNF-alpha inhibition provides an encouraging alternative. Here we summarise the current state in diagnosis and management of alcoholic hepatitis and briefly review the latest advances in pathophysiology that may lead to new therapeutic strategies for this difficult clinical condition. Data sources: Medline 1966-2005, EMBASE/Excerpta Medica 1980-2005, The Cochrane Library (2005 Issue 2) and contact with authors of published reports.

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Rev Prat. 2005 Sep 30;55(14):1539-48.
[Liver cirrhosis in adults: etiology and specific treatments]
[Article in French]
Fartoux L, Serfaty L.
Service d'hepatologie, hopital Saint-Antoine, 75571 Paris. laetitia.fartoux@sat.ap-hop.paris.fr

Cirrhosis is the result of chronic inflammation and of the progressive increase of fibrosis. In France, hepatitis C infection is the second cause of cirrhosis after alcohol abuse. The other causes of cirrhosis are: hepatitis B infection, genetic haemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, drug-induced cirrhosis, secondary biliary cirrhosis, Wilson's disease and al-antitrypsin deficiency. Etiological treatment is based upon: abstinence in case of alcoholic cirrhosis, the combination of pegylated interferon alpha (PEG IFN) with ribavirin in case of C viral cirrhosis, the PEG IFN and the nucleoside analogs in case of B viral cause; corticosteroids and immunosuppressive drugs in case of autoimmune cirrhosis; venesections in case of genetic haemochromatosis and stopping the drug in case of drug-induced cirrhosis. The complications of cirrhosis such as ascites, oesophageal varices, bleeding, hepatic encephalopathy and hepatocellular carcinoma mainly explain the high rate of morbidity and mortality. Liver transplantation is the established therapy for decompensated liver disease of any etiology significantly changed the outcome of patients with advanced cirrhosis.

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Rev Med Suisse. 2005 Sep 7;1(31):2026-8, 2030-1.
[Alcoholic and nonalcoholic steatohepatitis: the same disease! I. Diagnosis and mechanisms]
[Article in French]
Spahr L, Rubbia-Brandt L, Hadengue A.
Service de gastroenterologie et d'hepatologie, Hopitaux universitaires de Geneve. Laurent.Spahr@hcuge.ch

Alcoholic steatohepatitis includes steatosis, inflammatory changes and hepatocellular damage. In severe form, jaundice and hepatic failure persist for several weeks, while non severe alcoholic steatohepatitis may follow an insidious course towards cirrhosis. Except for alcohol consumption, nonalcoholic steatohepatitis shares histological features and pathogenic mechanisms with alcoholic steatohepatitis, and is associated to the development of cirrhosis over time. Thus, given the increasing epidemics of the metabolic syndrome in industrialized countries, it is likely that alcoholic cirrhosis has been overdiagnosed in the past years. Obesity, insulin resistance and the oxidative stress including iron-mediated oxidative stress are involved both in alcoholic and non-alcoholic steatohepatitis.

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Scand J Gastroenterol. 2005 Aug;40(8):972-9.
Magnesium supplementation and muscle function in patients with alcoholic liver disease: a randomized, placebo-controlled trial.
Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I.
Department of Medicine V, Aarhus University Hospital, Arhus, Denmark. niels@as.aaa.dk

OBJECTIVE: The study was undertaken in order to evaluate the effect of magnesium (Mg) supplementation on muscle contents of Mg, muscle strength, muscle mass and sodium, potassium pumps (Na,K-pumps) in patients with alcoholic liver disease. Retrospectively, patients were also stratified according to spironolactone treatment. MATERIAL AND METHODS: The study comprised a placebo-controlled, randomized trial in which 59 consecutive patients with alcoholic liver disease were treated with Mg intravenously and orally (12.5 mmol daily) or placebo for 6 weeks. Muscle content of Mg, maximum isokinetic muscle strength, skeletal muscle mass and muscle content of Na,K-pumps were measured before and after Mg supplementation. RESULTS: Muscle Mg did not increase during the trial (paired t-test), but Mg supplementation and the duration of pre-study spironolactone treatment were independent predictors of muscle Mg (multiple regression). Muscle strength increased by 14% during the trial (p<0.001) and muscle mass increased by 11% (p=0.05), but with no difference between placebo and Mg treatment. Spironolactone treatment was associated with a 33% increase in the content of Na,K-pumps (p<0.001). CONCLUSIONS: Six weeks of Mg supplementation did not increase muscle Mg, although Mg supplementation and spironolactone treatment were independent predictors of muscle Mg. The intervention had no effect on muscle strength and mass, but both increased during the study, probably owing to the general care and attendance to the patients.

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Transplant Proc. 2005 Jul-Aug;37(6):2614-5.
Mycophenolate mofetil monotherapy in liver transplantation.
Pierini A, Mirabella S, Brunati A, Ricchiuti A, Franchello A, Salizzoni M.
Liver Transplantation Centre, Molinette Hospital, Turin, Italy.

AIM: Calcineurin inhibitors (CI) are associated with significant morbidity in transplant recipients. The aim of this study was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) monotherapy in liver transplantation (LT). METHODS: We analysed 32 patients (24 males, 8 female, of mean age 55.7 years) who underwent LT between 1994 and 2003. In 29 patients immunosuppressive therapy was cyclosporine; in three patients it was tacrolimus. Eleven patients were submitted for LT due to hepatitis B cirrhosis; eight for hepatitis C cirrhosis, six for alcoholic cirrhosis, and seven for other diseases. In these patients, MMF was added gradually, simultaneously reducing the dosage of CI up to complete withdrawal. We considered the efficacy (decrease in serum creatinine) and the incidence of complications (acute and chronic rejection, leukopenia, diarrhea). RESULTS: Patients were converted to MMF after a median of 50 months after LT. MMF monotherapy was started after a median of 9 months in association with CI. Indications for switch to MMF monotherapy were adverse effects of CI (renal disfunction in 30 patients) and de novo tumoral evidence after LT in two patients. Median dosage of MMF was 750 mg twice daily (500-1500 mg). There was a statistically significant decrease in serum creatinine levels (2.02-1.7 mg/dL; P = .0001). Side effects were: leukopenia in five of 32 patients (15.6%), diarrhea in four of 32 patients (12.5%), and one acute rejection. CONCLUSION: MMF monotherapy improved renal function and was not associated with a significant risk of allograft rejection. Side effects were mild with dose regimens up to 750 mg twice daily.

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Eur J Gastroenterol Hepatol. 2005 Jul;17(7):759-62.
Bilirubin response to corticosteroids in severe alcoholic hepatitis.
Morris JM, Forrest EH.
Victoria Infirmary, Department of Gastroenterology, Glasgow, UK.

INTRODUCTION: There is little consensus on the management of alcoholic hepatitis, particularly with regard to corticosteroid therapy. We aimed to identify those patients who respond to corticosteroid therapy for alcoholic hepatitis. METHODS: We identified 37 patients with alcoholic hepatitis with a modified Maddrey's discriminant function of 32 or greater. We assessed their outcomes at 28 and 56 days treatment after admission relative to their response to corticosteroid treatment. RESULTS: Corticosteroid treated patients experienced a change in the serum bilirubin concentration after 6-9 days of -23.0+/-4.7%. Overall, the mortality was 18.9 and 35.1% at 28 and 56 days. Response to corticosteroids was defined as a 25% fall in serum bilirubin after 6-9 days of treatment. The mortality of the non-responders was 36.8% and 57.9% at 28 and 56 days compared with 0% (P=0.0148) and 11.1% (P=0.0084) for corticosteroid responders. CONCLUSIONS: Patients with a 25% fall in bilirubin after 6-9 days of corticosteroid therapy have a significant and sustained improvement in outcome.

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J Clin Gastroenterol. 2005 Jul;39(6):540-3.
Beneficial effects of a probiotic VSL#3 on parameters of liver dysfunction in chronic liver diseases.
Loguercio C, Federico A, Tuccillo C, Terracciano F, D'Auria MV, De Simone C, Del Vecchio Blanco C.
Department of Internistica Clinica e Sperimentale F. Magrassi e A. Lanzara, Inter-University Research Center on Foods, Nutrition, and Gastrointestinal Tract (CIRANAD), Second University of Naples, Naples, Italy. carmelina.loguercio@unina2.it

OBJECTIVES: To evaluate whether chronic therapy with probiotics affects plasma levels of cytokines and oxidative/nitrosative stress parameters, as well as liver damage, in patients with various types of chronic liver disease. PATIENTS AND METHODS: A total of 22 nonalcoholic fatty liver disease (NAFLD) and 20 alcoholic liver cirrhosis (AC) patients were enrolled in the study and compared with 36 HCV-positive patients with chronic hepatitis without (20, CH) or with (16, CC) liver cirrhosis. All patients were treated with the probiotic VSL#3. Routine liver tests, plasma levels of tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-6 and -10, malondialdehyde (MDA), and 4-hydroxynonenal (4-HNE), S-nitrosothiols (S-NO), were evaluated on days -30, 0, 90, and 120. RESULTS: Treatment with VSL#3 exerted different effects in the various groups of patients: in NAFLD and AC groups, it significantly improved plasma levels of MDA and 4-HNE, whereas cytokines (TNF-alpha, IL-6, and IL-10) improved only in AC patients. No such effects were observed in HCV patients. Routine liver damage tests and plasma S-NO levels were improved at the end of treatment in all groups. CONCLUSIONS: Results of the study suggest that manipulation of intestinal flora should be taken into consideration as possible adjunctive therapy in some types of chronic liver disease.

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Eur J Gastroenterol Hepatol. 2005 Jul;17(7):759-62.
Bilirubin response to corticosteroids in severe alcoholic hepatitis.
Morris JM, Forrest EH.
Victoria Infirmary, Department of Gastroenterology, Glasgow, UK.

INTRODUCTION: There is little consensus on the management of alcoholic hepatitis, particularly with regard to corticosteroid therapy. We aimed to identify those patients who respond to corticosteroid therapy for alcoholic hepatitis. METHODS: We identified 37 patients with alcoholic hepatitis with a modified Maddrey's discriminant function of 32 or greater. We assessed their outcomes at 28 and 56 days treatment after admission relative to their response to corticosteroid treatment. RESULTS: Corticosteroid treated patients experienced a change in the serum bilirubin concentration after 6-9 days of -23.0+/-4.7%. Overall, the mortality was 18.9 and 35.1% at 28 and 56 days. Response to corticosteroids was defined as a 25% fall in serum bilirubin after 6-9 days of treatment. The mortality of the non-responders was 36.8% and 57.9% at 28 and 56 days compared with 0% (P=0.0148) and 11.1% (P=0.0084) for corticosteroid responders. CONCLUSIONS: Patients with a 25% fall in bilirubin after 6-9 days of corticosteroid therapy have a significant and sustained improvement in outcome.

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Liver Transpl. 2005 Jun;11(6):679-83.
Tobacco use following liver transplantation for alcoholic liver disease: an underestimated problem.
DiMartini A, Javed L, Russell S, Dew MA, Fitzgerald MG, Jain A, Fung J.
Department of Psychiatry, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. dimartiniaf@upmc.edu

Alcohol and tobacco use commonly co-occur, with at least 90% of those with an alcohol problem also using tobacco. Thus, 3 years ago when we discovered higher rate of late deaths due to lung and oropharyngeal cancer in patients who had received a transplant for alcoholic liver disease (ALD), we hypothesized that these patients were continuing to expose themselves to tobacco after liver transplantation (post-LTX) and that this behavior was increasing their risk for cancer. We subsequently began a prospective investigation of post-LTX tobacco use in patients having undergone LTX for ALD (n = 172). For 33 recipients we had data starting from our first assessment at 3 months post-LTX and for this subgroup we report on the details of the timing of tobacco use resumption and the redevelopment of nicotine addiction. We found that on average more than 40% are smoking across all time periods. ALD recipients resume smoking early post-LTX, increase their consumption over time, and quickly become tobacco dependent. These data highlight an underrecognized serious health risk for these patients and demonstrate our need for more stringent clinical monitoring and intervention for tobacco use in the pre- and post-LTX periods.

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J Hepatol. 2005 Jul;43(1):142-8. Epub 2005 Apr 9.
Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis.
Sen S, Mookerjee RP, Cheshire LM, Davies NA, Williams R, Jalan R.
Liver Failure Group, Institute of Hepatology, University College London Medical School, 69-75 Chenies Mews, London WC1E 6HX, UK.

BACKGROUND/AIMS: In patients with alcoholic hepatitis (AH), inflammation contributes to the severity of portal hypertension. This study evaluates the acute effects of albumin dialysis, using the Molecular Adsorbents Recirculating System (MARS), on portal pressure in AH. METHODS: Eleven patients with AH and portal hypertension were treated with MARS (n=8) or haemofiltration (n=3). All patients had associated organ failure manifested by hepatic encephalopathy (Grade 2 or more) or renal failure. Hepatic venous pressure gradient (HVPG) was measured before, during and after the treatment session. RESULTS: A rapid significant reduction of HVPG was observed by 6 h (falling by > or =20% in 7/8 patients, reaching 12 mmHg in 6/8), which was sustained up to 18 h after stopping dialysis. Similar rapid sustained improvements of systemic haemodynamics were also observed. No changes occurred in three patients receiving haemofiltration alone. CONCLUSIONS: Albumin dialysis produces clinically significant, acute reduction in portal pressure but the mechanism by which this effect is achieved is not clear. Our results suggest that MARS may be a useful adjunct in management of portal hypertension, particularly in patients with severe AH with associated organ failure.

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Transpl Int. 2005 May;18(5):491-8.
Liver transplantation in alcoholic patients.
Burra P, Lucey MR.
Section of Gastroenterology, Liver Gastroenterology Transplantation, Department of Surgical and Gastroenterological Sciences, University Hospital, University of the Study, Padua, Italy. burra@unipd.it

Alcoholic liver disease is one of the most common causes of cirrhosis and indications for orthotopic liver transplantation in Europe and North America. The reluctance to transplant alcoholics stems in part from the view that alcoholics bear responsibility for their illness. There is also the perception that the alcoholic person is likely to relapse into alcohol use after transplantation and thereby damage the allograft. In this review, we considered the evaluation for and outcome of liver transplantation in alcoholics with special attention to the specific risks of alcohol relapse, to show that alcoholism should be considered like other co-morbid states rather than as a moral flaw.

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Curr Opin Gastroenterol. 2005 May;21(3):323-30.
Alcohol and the liver.
Willner IR, Reuben A.
Liver Transplantation Division of Gastroenterology/Hepatology Medical University of South Carolina, Charleston, 29425, USA. willneri@musc.edu

PURPOSE OF REVIEW: To highlight salient recent discoveries and results of clinical trials in alcoholic liver disease (ALD). The burden of care for ALD patients is hefty and the prevalence of alcohol abuse may be increasing in both the developed and the underdeveloped world. RECENT FINDINGS: Molecular mechanisms of alcoholism are being identified but not of the predisposition to alcoholic liver injury, except perhaps for polymorphism of a cytotoxic T-cell antigen. The Mayo End-stage Liver Disease (MELD) score performs well in assessing the prognosis of ALD; serological biomarkers for predicting ALD outcome are of uncertain value. Concomitant liver disease (e.g., obesity, hepatitis C, and iron overload) aggravates the severity of ALD; conversely, alcohol abuse may be a cryptic co-factor in some cases of non-alcoholic fatty liver. For alcoholic hepatitis, nutritional support is the mainstay of treatment; steroids are considered by some (but not all) as safe and effective therapy, whereas manipulations of tumor necrosis factor-alpha activity have been disappointing, or of unproven benefit at best. In liver transplantation for ALD, methods are being devised to monitor recidivism and to ameliorate its risk and that of co-morbid psychiatric conditions. SUMMARY: Much of the pathogenesis of ALD has been identified and headway has been made in predicting its prognosis. However, much remains to be done to elucidate the molecular genetics of the risk of developing ALD and in formulating safe, effective therapies for alcoholic hepatitis.

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Ann Transplant. 2005;10(1):38-43.
Wasting your organ with your lifestyle and receiving a new one?
Berlakovich GA.
Department of Transplant Surgery, University of Vienna, Austria. gabriela.berlakovich@meduniwien.ac.at

Alcoholic liver disease is the leading cause of end-stage liver disease and the second most common indication for liver transplantation (OLT) in the United States and Europe, with the number of patients receiving transplants each year representing about 5% of the estimated deaths from alcoholic cirrhosis. Long-term patient survival rates compare favorable with those for other chronic liver diseases. Nevertheless, there remains a certain ambivalence about the role of OLT in patients suffering from alcoholic cirrhosis, based partly on concerns regarding alcohol relapse and functional outcome post-transplant in an era of donor organ shortage and priority setting. This review article focuses especially on compliance and social rehabilitation of patients who have undergone OLT for alcoholic cirrhosis. Furthermore, pre-transplant evaluation and selection of potential candidates are discussed and guidelines are given to clarify the role of OLT in the management of patients suffering from alcoholic cirrhosis. It appears very important to mention that alcoholism is not a fault but represents a disease, and provided that the underlying disease can be treated, consequent disease (end-stage liver disease) should be treated, too.

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Cochrane Database Syst Rev. 2005 Apr 18;(2):CD003620.
Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases.
Rambaldi A, Jacobs B, Iaquinto G, Gluud C.
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7102, H:S Rigshospitalet,, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DENMARK, DK-2100.

BACKGROUND: Alcohol and hepatotoxic viruses cause the majority of liver diseases. Randomised clinical trials have assessed whether extracts of milk thistle, Silybum marianum (L) Gaertneri, have any effect in patients with alcoholic and/or hepatitis B or C virus liver diseases. OBJECTIVES: To assess the beneficial and harmful effects of milk thistle or milk thistle constituents versus placebo or no intervention in patients with alcoholic liver disease and/or viral liver diseases (hepatitis B and hepatitis C). SEARCH STRATEGY: TheCochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and full text searches were combined (December 2003). Manufacturers and researchers in the field were contacted. SELECTION CRITERIA: Only randomised clinical trials in patients with alcoholic and/or hepatitis B or C virus liver diseases (acute and chronic) were included. Interventions encompassed milk thistle at any dose or duration versus placebo or no intervention. The trials could be double blind, single blind, or unblinded. The trials could be unpublished or published and no language limitations were applied. DATA COLLECTION AND ANALYSIS: The primary outcome measure was mortality. Binary outcomes are reported as relative risks (RR) with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality. MAIN RESULTS: Thirteen randomised clinical trials assessed milk thistle in 915 patients with alcoholic and/or hepatitis B or C virus liver diseases. The methodological quality was low: only 23% of the trials reported adequate allocation concealment and only 46% were considered adequately double-blinded. Milk thistle versus placebo or no intervention had no significant effect on mortality (RR 0.78, 95% CI 0.53 to 1.15), complications of liver disease (RR 0.95, 95% CI 0.83 to 1.09), or liver histology. Liver-related mortality was significantly reduced by milk thistle in all trials (RR 0.50, 95% CI 0.29 to 0.88), but not in high-quality trials (RR 0.57, 95% CI 0.28 to 1.19). Milk thistle was not associated with a significantly increased risk of adverse events (RR 0.83, 95% CI 0.46 to 1.50). AUTHORS' CONCLUSIONS: Our results question the beneficial effects of milk thistle for patients with alcoholic and/or hepatitis B or C virus liver diseases and highlight the lack of high-quality evidence to support this intervention. Adequately conducted and reported randomised clinical trials on milk thistle versus placebo are needed.

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Gastroenterology. 2005 Apr;128(4):882-90.
Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival.
Morgan TR, Weiss DG, Nemchausky B, Schiff ER, Anand B, Simon F, Kidao J, Cecil B, Mendenhall CL, Nelson D, Lieber C, Pedrosa M, Jeffers L, Bloor J, Lumeng L, Marsano L, McClain C, Mishra G, Myers B, Leo M, Ponomarenko Y, Taylor D, Chedid A, French S, Kanel G, Murray N, Pinto P, Fong TL, Sather MR.
VA Long Beach Healthcare Systems, Long Beach, CA 90822, USA. timothy.morgan@med.va.gov

BACKGROUND & AIMS: Colchicine improved survival and reversed cirrhosis in several small clinical trials. We compared the efficacy and safety of long-term colchicine, as compared with placebo, in patients with advanced alcoholic cirrhosis. METHODS: Five hundred forty-nine patients with advanced (Pugh B or C) alcoholic cirrhosis were randomized to receive either colchicine 0.6 mg twice per day (n = 274) or placebo (n = 275). Treatment lasted from 2 to 6 years. The primary outcome was all-cause mortality. Secondary outcomes were liver-related morbidity and mortality. Liver biopsy was requested prior to entry and after 24 months of treatment. RESULTS: Attendance at scheduled clinic visits and adherence with study medication were similar in colchicine and placebo groups. Alcohol intake was less than 1 drink per day in 69% of patients. In an intention-to-treat analysis, all-cause mortality was similar in colchicine (49%) and placebo (45%) patients (P = .371). Mortality attributed to liver disease was 32% in colchicine and 28% in placebo patients (P = .337). Fewer patients receiving colchicine developed hepatorenal syndrome. In 54 patients with repeat liver biopsies after 24 or more months of treatment, cirrhosis improved to septal fibrosis in 7 patients (3 colchicine, 4 placebo) and to portal fibrosis in 1 patient (colchicine). CONCLUSIONS: In patients with advanced alcoholic cirrhosis, colchicine does not reduce overall or liver-specific mortality. Liver histology improves to septal fibrosis in a minority of patients after 24 months of treatment, with similar rates of improvement in patients receiving placebo and colchicine. Colchicine is not recommended for patients with advanced alcoholic cirrhosis.

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Clin Liver Dis. 2005 Feb;9(1):171-81.
Liver transplantation for alcoholic liver disease.
Zetterman RK.
Nebraska-Western Iowa VA Health Care System, 4101 Woolworth Avenue, Omaha, NE 68105, USA. rzetterm@unmc.edu

Patients with end-stage alcoholic liver disease should be considered for liver transplantation. A careful pretransplant evaluation must be undertaken to assess for both medical and psychiatric factors that will continue to require attention following transplantation. Although most programs require at least 6 months of ethanol abstinence before consideration of liver transplantation, there is little evidence that this conclusively predicts a reduction in recidivism. Most programs continue to exclude those with alcoholic hepatitis. Postoperatively, attention to psychiatric issues, recidivism, compliance, and assessment for tumors, especially squamous cell carcinomas, should be undertaken.

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Clin Liver Dis. 2005 Feb;9(1):135-49.
Long-term management of alcoholic liver disease.
Wakim-Fleming J, Mullen KD.
Case Western Reserve School of Medicine, 2580 Metrohealth Drive, Room G-632A, Cleveland, OH 44109, USA. jwfleming@metrohealth.org

Despite the epidemics of viral hepatitis C and nonalcoholic fatty liver disease, alcohol remains one of the major causes of liver disease. Commonly, hepatitis C and other liver diseases are found in association with alcohol consumption. This association in many instances is noted to accelerate the progression of liver disease. In many respects, the long-term management of alcoholic liver disease is not dissimilar from the long-term management of patients with cirrhosis from other etiologies. One major element is the abstinence of alcohol use. The ability to maintain sobriety has a major impact on the outcome of patients with alcoholic cirrhosis because maintaining abstinence can lead to significant regression of fibrosis and possibly early cirrhosis. Similarities in managing patients with cirrhosis due to alcohol or cirrhosis from other causes include vaccination to prevent superimposed viral hepatitis and screening for esophageal varices and hepatocellular carcinoma with subsequent appropriate therapy.

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Hepatobiliary Pancreat Dis Int. 2005 Feb;4(1):12-7.
Treatment of patients with alcoholic liver disease.
Zhang FK, Zhang JY, Jia JD.
Liver Research Center, Beijing Friendship Hospital, Capital University of Medical Sciences, Beijing 100050, China. frankliver@yahoo.com.cn

BACKGROUND: The proportion of alcoholic liver disease among all kinds of liver diseases in China is increasing. Recent research has elucidated the mechanisms of alcohol-induced liver injury and offered the prospect of advances in the management of alcoholic liver disease. DATA RESOURCES: Searching MEDLINE (1982-July 2004) for papers on alcoholic liver disease, especially those on the treatment of alcoholic liver disease. RESULTS: Abstinence remains the cornerstone of management of all forms of alcoholic liver disease. Nutritional support therapy is also a basal treatment. Corticosteroids may be benefitial for some severe alcoholic hepatitis. None of other measures including anti-inflammatory agents, antioxidants or colchicine has been shown consistently to improve the course of alcoholic liver damage. Ultimately, liver transplantation remains an option for selected patients with liver failure due to chronic alcoholic liver disease. CONCLUSIONS: Abstinence and nutritional support remain the base management of alcoholic liver disease. Corticosteroid is efficient for some severe alcoholic hepatitis. Anti-inflammatory agents and antioxidants may be of benefit but need further studies. The efficacy of other measures including the use of colchicine and propylthiouracil is controversial. Liver transplantation remains an option for selected patients with liver failure.

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Acta Gastroenterol Belg. 2005 Jan-Mar;68(1):19-25.
Longitudinal prospective study on quality of life and psychological distress before and one year after liver transplantation.
Burra P, De Bona M, Canova D, Feltrin A, Ponton A, Ermani M, Brolese A, Rupolo G, Naccarato R.
Department of Surgical and Gastroenterological Sciences, University of Padua, Padua, Italy. burra@unipd.it

BACKGROUND: The impact of liver disease and medical complications on quality of life (QOL) and psychological distress before and after liver transplantation (LT) is a matter of growing interest. METHODS: In a longitudinal prospective study, perceived QOL (LEIPAD Quality of Life test) and psychological distress (Brief Symptom Inventory, BSI) were assessed in 25 cirrhotic patients when they were listed for LT and 1, 3, 6 and 12 months after LT. Patients were also evaluated for medical complications and blood levels of immunosuppressive agents. RESULTS: Overall QOL and psychological distress improved significantly and rapidly in most domains from the first month and up to a year after LT. Medical complications and immunosuppressive agents did not correlate with any changes in QOL and psychological distress after LT. When patients were divided according to liver disease etiology: 1. HCV patients listed for LT had worse QOL levels than the group of patients as a whole or the alcoholic liver disease (ALD) patients; 2. HCV patients reported a significant improvement in QOL only 6 and 12 months after LT, and still suffered more psychological distress 12 months after surgery; 3. in ALD patients, overall QOL and psychological distress improved significantly at all follow-up points after LT; 4. HCV patients reported a worse QOL and greater psychological distress 1 and 3 months after LT than the group as a whole or the ALD patients (p < 0.05). CONCLUSIONS: Liver transplantation improves QOL and psychological distress in most recipients, but not in the early stages after LT in patients transplanted for HCV cirrhosis.

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Curr Treat Options Gastroenterol. 2004 Dec;7(6):451-458.
Alcoholic Hepatitis.
Agarwal K, Kontorinis N, Kontorinis N, Dieterich DT, Dieterich DT.
Department of Medicine, Mount Sinai Medical Center, One Gustave Levy Place, New York, NY 10029-6574, USA.

Alcoholic hepatitis (AH) is a common disease associated with significant morbidity and mortality. Most often the diagnosis is suggested by a history of heavy alcohol excess in a patient with features of hepatic decompensation. In its purest form, AH is a histologic diagnosis of acute hepatic inflammation in response to alcohol. The primary objective of treatment for AH is to support long-term alcohol abstinence and to achieve adequate nutrition with lifestyle modification; goal setting and education are integral to long-term medical management. Severity at presentation (calculated by way of the Maddrey score) determines outcome. Patients with AH represent a heterogeneous group with regard to severity and pathogenesis, with various therapeutic interventions assessed in patients with severe AH. To date, corticosteroids have been studied most, and despite remaining controversial, warrant a place in the treatment of selected patients. Recent advances in unraveling the aspects of disease pathogenesis in AH have raised the possibility of targeted therapies, such as anti-tumor necrosis factor-a monoclonals and pentoxifylline. Orthotopic liver transplantation is not recommended for patients with severe acute AH, as most have an unclear long-term prognosis in the context of ongoing excess alcohol ingestion at presentation.

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Eur J Gastroenterol Hepatol. 2004 Nov;16(12):1375-80.
Combining steroids with enteral nutrition: a better therapeutic strategy for severe alcoholic hepatitis? Results of a pilot study.
Alvarez MA, Cabre E, Lorenzo-Zuniga V, Montoliu S, Planas R, Gassull MA.
Department of Gastroenterology, University Hospital Germans Trias i Pujol, Badalona, Catalonia, Spain.

BACKGROUND: Results of a previous randomized controlled trial comparing the outcome of patients with severe alcoholic hepatitis treated with total enteral nutrition (TEN) or corticosteroids suggest that these treatments act through different mechanisms and may be complementary. We report a pilot study of combined treatment with TEN and a shorter course of steroids in patients with severe alcoholic hepatitis. METHODS: Thirteen patients with severe alcoholic hepatitis were treated with systemic steroids and TEN. Steroid therapy started with 40 mg oral prednisolone daily, and was progressively tapered as soon as both serum bilirubin and prothrombin time decreased below 50% of their baseline values. TEN (2000 kcal, or 8374 kJ, daily) was administered throughout the hospital stay. Patients were followed for at least 12 months or until death. RESULTS: Tapering of prednisolone dose could be started after a mean (SD) of 15.4 (3.8) days, whereas TEN was maintained for 22 (3.8) days. TEN was tolerated in 10 of the 13 patients. The major adverse event attributable to therapy was hyperglycemia requiring insulin therapy, which occurred in 12 of 13 patients. Only two patients (15%) died during the treatment period. Another patient died within the first 2 months of follow-up. In no case was the death due to infectious complications, despite two-thirds of patients developing infections during the treatment period. Infections during follow-up occurred only in three patients. CONCLUSION: This pilot study suggests that TEN associated with a short course of steroids could be a good therapeutic strategy for severe alcoholic hepatitis. This possibility deserves investigation in a randomized controlled trial.

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Alcohol. 2004 Aug;34(1):3-8.
Role of fatty liver, dietary fatty acid supplements, and obesity in the progression of alcoholic liver disease: introduction and summary of the symposium.
Purohit V, Russo D, Coates PM.
Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5635 Fishers Lane, Room 2035, Bethesda, MD 20892-9304, USA.

Alcoholic liver disease is a major cause of illness and death in the United States. In the initial stages of the disease, fat accumulation in hepatocytes leads to the development of fatty liver (steatosis), which is a reversible condition. If alcohol consumption is continued, steatosis may progress to hepatitis and fibrosis, which may lead to liver cirrhosis. Alcoholic fatty liver has long been considered benign; however, increasing evidence supports the idea that it is a pathologic condition. Blunting of the accumulation of fat within the liver during alcohol consumption may block or delay the progression of fatty liver to hepatitis and fibrosis. To achieve this goal, it is important to understand the underlying biochemical and molecular mechanisms by which chronic alcohol consumption leads to fat accumulation in the liver and fatty liver progresses to hepatitis and fibrosis. In addition to alcohol consumption, dietary fatty acids and obesity have been shown to affect the degree of fat accumulation within the liver. Again, it is important to know how these factors modulate the progression of alcoholic liver disease. The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of Fatty Liver, Dietary Fatty Acid Supplements, and Obesity in the Progression of Alcoholic Liver Disease" in Bethesda, Maryland, USA, October 2003. The following is a summary of the symposium. Alcoholic fatty liver is a pathologic condition that may predispose the liver to further injury (hepatitis and fibrosis) by cytochrome P450 2E1 induction, free radical generation, lipid peroxidation, nuclear factor-kappa B activation, and increased transcription of proinflammatory mediators, including tumor necrosis factor-alpha. Increased acetaldehyde production and lipopolysaccharide-induced Kupffer cell activation may further exacerbate liver injury. Acetaldehyde may promote hepatic fat accumulation by impairing the ability of peroxisome proliferator-activated receptor alpha to bind DNA, and by increasing the synthesis of sterol regulatory binding protein-1. Unsaturated fatty acids (corn oil, fish oil) exacerbate alcoholic liver injury by accentuating oxidative stress, whereas saturated fatty acids are protective. Polyenylphosphatidylcholine may prevent liver injury by down-regulating cytochrome P450 2E1 activity, attenuating oxidative stress, reducing the number of activated hepatic stellate cells, and up-regulating collagenase activity. Nonalcoholic steatohepatitis may develop through several mechanisms, such as oxidative stress, mitochondrial dysfunction and associated impaired fat metabolism, dysregulated cytokine metabolism, insulin resistance, and altered methionine/S-adenosylmethionine/homocysteine metabolism. Obesity (adipose tissue) may contribute to the development of alcoholic liver disease by generating free radicals, increasing tumor necrosis factor-alpha production, inducing insulin resistance, and producing fibrogenic agents, such as angiotensin II, norepinephrine, neuropeptide Y, and leptin. Finally, alcoholic fatty liver transplant failure may be linked to oxidative stress. In vitro treatment of fatty livers with interleukin-6 may render allografts safer for clinical transplantation.

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Liver Transpl. 2004 Oct;10(10 Suppl 2):S31-8.
Liver transplantation for alcoholic liver disease: current concepts and length of sobriety.
Lim JK, Keeffe EB.
Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.

1. The 1-year and 5-year actuarial survival rates following liver transplantation for patients with alcoholic liver disease are 82% and 68%, respectively, in the United States and 85% and 70%, respectively, in Europe. These survival rates are similar to the outcomes of patients who undergo transplantation for other types of chronic liver disease. 2. Posttransplant improvements in health-related quality of life are similar in patients who undergo transplantation for alcoholic liver disease compared to those who undergo transplantation for other causes of end-stage liver disease. 3. Approximately 20% of patients who undergo transplantation for alcoholic liver disease use alcohol posttransplant, with one-third of these individuals exhibiting repetitive or heavy drinking. Surprisingly, little evidence exists to document a significant detrimental effect on graft or patient survival associated with resumption of drinking. 4. There are few reliable predictors of relapse in alcoholic patients after liver transplantation. Although not supported by all studies, abstinence of fewer than 6 months prior to transplantation may be a reasonable predictor of recidivism and is widely employed as a criterion for listing for liver transplantation. There are no good data to determine if some patients with sobriety fewer than 6 months might benefit from liver transplantation.

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Gastroenterol Clin Biol. 2004 Oct;28(10 Pt 1):845-51.
Predictive factors of alcohol relapse after orthotopic liver transplantation for alcoholic liver disease.
Miguet M, Monnet E, Vanlemmens C, Gache P, Messner M, Hruskovsky S, Perarnau JM, Pageaux GP, Duvoux C, Minello A, Hillon P, Bresson-Hadni S, Mantion G, Miguet JP.
Hopital Jean Minjoz, Besancon. scoffre@club-internet.fr

OBJECTIVES: The objective of this prospective study was to determine whether sociological and/or alcohol-related behavioral factors could be predictive of relapse after orthotopic liver transplantation for alcoholic liver disease. METHODS: Fifty-five liver-transplanted patients out of a series of 120 alcoholic cirrhotic patients were enrolled in a randomized prospective study. This study was initially designed to compare the 2 year survival in intent-to-transplant patients versus in-intent-to-use conventional treatment patients. For all patients, an identical questionnaire was completed at inclusion, and every 3 months for 5 years to collect data on alcohol-related behavior factors. RESULTS: Fifty-one patients fulfilled the criteria for the study. The mean follow-up was 35.7 months (range: 1-86). Rate of alcohol relapse was 11% at one year and 30% at 2 years. Alcohol intake above 140 g a week was declared by 11% and 22% of patients at one and 2 years, respectively. The only variable leading to a significantly lower rate of relapse was abstinence for 6 months or more before liver transplantation (23% vs 79%, P=0.0003). This variable was also significant for patients whose alcohol intake was greater than 140 g per week (P=0.003) (adjusted relative risk=5.5; 95%CI=1.3-24.5; P=0.02). Multivariate analysis (Cox model) showed that abstinence for 6 months or more before liver transplantation was the unique predictive variable. CONCLUSION: In this prospective study of 51 patients transplanted for alcoholic liver disease, abstinence before liver transplantation was the only predictive factor of alcohol relapse after liver transplantation.

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Scott Med J. 2004 Aug;49(3):84-7.
The impact of specialist management of jaundiced alcoholic liver disease patients.
Forrest EH.
Department of Gastroenterology, Victoria Infirmary, Glasgow. Ewan.Forrest@gvic.scot.nhs.uk

BACKGROUND: Patients with alcoholic liver disease (ALD) presenting with jaundice have advanced chronic ALD and/or acute alcoholic hepatitis. Their prognosis is poor. These patients may be managed by General Medical physicians (GM) or by Gastroenterologists (GE). AIM: This study aimed to retrospectively assess the differences in management and outcome of jaundiced ALD between GM and GE. PATIENTS AND METHODS: Patients with a serum bilirubin greater than 80 mmol/l on admission and a history of alcohol excess until within three weeks of admission were identified retrospectively. In particular the use of corticosteroids (CS), nutritional support (N) and the use of broad-spectrum antibiotics (A/b) were noted. RESULTS: 97 patients were identified, 62 managed by GE. Differences were apparent between GE and GM managed patients with respect to CS (p = 0.017), N (p < 0.001) and A/b (p < 0.001). The overall mortality was 27.8%, 34.0%, and 37.1% at 28, 56, and 84 days respectively. Mortality for patients with a Discriminant Function approximately 32 was greater in GM managed patients compared with GE at 28 (p = 0.006), 56 (p = 0.013), and 84 days (p = 0.036). CONCLUSION: Differences exist between the management of jaundiced ALD between GM and GE. Such differences may translate into improved outcomes.

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Ther Umsch. 2004 Aug;61(8):505-12.
[Alcoholic and non-alcoholic steatohepatitis]
[Article in German]
Dufour JF, Oneta CM.
Institut fur klinische Pharmakologie der Universitat Bern. jf.dufour@ikp.unibe.ch

Chronic aethylism has always been a major social as well as health problem. It may lead, at least in some patients, to steatohepatitis (ASH) which is known to progress to cirrhosis more rapidly. Because of the fact that the prevalence of obesity in association with the metabolic syndrome (insulin resistance) is strikingly increasing in the Western world, we will more and more often be faced with a second form of steatohepatitis, the so called non-alcoholic steatohepatitis (NASH). Clinical differentiation between these two entities may often be difficult. The use of the CAGE-questions as well as interviewing family members can help to indentify hidden alcohol abuse. Clinically, the presence of both diseases can only be speculated. To get the diagnosis, liver biopsy must be performed to show the typical histologic feature of fatty liver with hepatocyte necrosis as well as infiltration of polymorphcellular leukocytes. Histology cannot differentiate between ASH and NASH. Therefore, similar pathogenetic mechanisms are supposed. However, therapeutic approaches are different. Treatment of choice in ASH is alcohol abstinence, that of NASH the reduction of insulin resistance, primarily by weight loss.

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Semin Liver Dis. 2004 Aug;24(3):289-304.
Nutrition and alcoholic liver disease.
Halsted CH.
Department of Internal Medicine and Nutrition, University of California Davis, Davis, California 95616, USA. chhalsted@ucdavis.edu

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.

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Semin Liver Dis. 2004 Aug;24(3):249-55.
Transplantation in the alcoholic patient.
Watt KD, McCashland TM.
Department of Internal Medicine and Hepatology, University of Nebraska Medical Center, Omaha, Nebraska 68198-3285, USA.

Alcoholic liver disease (ALD) is the second leading indication for transplantation in the United States. Most transplant programs in the United States require a minimum of 6 month's abstinence before transplantation is performed. Most studies have shown a recidivism rate of between 20 and 30% by 2 years after orthotopic liver transplantation (OLT). Higher rates of recidivism are reported if pre-OLT abstinence was < 6 months. The impact of recidivism on patient and graft survival is not clear because most reports include patients who consume alcohol in small amounts or infrequently. Equal post-OLT survival for ALD patients and non-ALD patients has been demonstrated, and ALD patients are not thought to suffer greater morbidity post transplant than non-ALD patients. Careful pretransplant assessment for concomitant medical and psychosocial ailments associated with alcoholism is important. Posttransplant monitoring for cardiovascular disease and withdrawal syndromes is required in the early postoperative setting, whereas monitoring for recidivism and malignancy are late postoperative issues.

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Semin Liver Dis. 2004 Aug;24(3):233-47.
Diagnosis and therapy of alcoholic liver disease.
Levitsky J, Mailliard ME.
University of Nebraska College of Medicine, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.

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-alpha) 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.

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Liver Transpl. 2004 Jul;10(7):886-97.
Survival after liver transplantation in the United States: A disease-specific analysis of the UNOS database.
Roberts MS, Angus DC, Bryce CL, Valenta Z, Weissfeld L.
Section of Decision Sciences and Clinical Systems Modeling, Division of General Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA.

Our goal was to describe disease-specific survival and the clinical variables that predict survival in a large national cohort of adult liver transplant recipients. Data on 17,044 adult patients who received an initial orthotopic liver transplant between 1990 and 1996 with follow-up through 1999 was obtained from the United Network for Organ Sharing (UNOS). Disease-specific Kaplan-Meier survival plots and Cox Proportional Hazards models were estimated, and differences in the clinical characteristics of patients at the time of transplantation by disease were examined. Overall posttransplant survival currently exceeds 85% in the first year and is approaching 75% at 5 years. Unadjusted Kaplan-Meier survival is improved for recipients who are younger, female, and in better clinical condition. Survival is a function of disease and level of illness: cancer, fulminant liver failure, alcoholic liver disease, and the hepatitidies have the poorest prognosis, while primary billiary cirrohsis and sclerosing cholangitis have the best. Recipients who were outpatients before transplantation have longer survival than those transplanted from the hospital or intensive care unit. Although the model for end-stage liver disease (MELD) score was designed to predict pretransplant survival, patients with higher MELD scores have poorer posttransplant survival, but the MELD score is less predictive than the specific disease. Differences in disease-specific survival are partially explained by differences in disease severity at the time of transplantation. In conclusion, Disease-specific survival models indicate that there remains tremendous variability in survival as a function of underlying liver disease. However, a significant portion of the difference in survival between diseases arises from differences in clinical characteristics at the time of transplantation. (Liver Transpl 2004;10:886-897.)

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Hepatology. 2004 May;39(5):1390-7.
A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.
Naveau S, Chollet-Martin S, Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broet P, Emilie D; Foie-Alcool group of the Association Francaise pour l'Etude du Foie.
Services d'Hepato-Gastroenterologie, Hopital Antoine Beclere, Clamart, Assistance Publique-Hopitaux de Paris, France. sylvie.naveau@abc.ap-hop-paris.fr

Tumor necrosis factor-alpha (TNF-alpha) may contribute to the progression of acute alcoholic hepatitis (AAH). The aim of this study was to evaluate the efficacy of an association of infliximab and prednisolone at reducing the 2-month mortality rate among patients with severe AAH. Patients with severe AAH (Maddrey score >/=32) were randomly assigned to group A receiving intravenous infusions of infliximab (10 mg/kg) in weeks 0, 2, and 4; or group B receiving a placebo at the same times. All patients received prednisolone (40 mg/day) for 28 days. Blood neutrophil functional capacities were monitored over 28 days. After randomization of 36 patients, seven patients from group A and three from group B died within 2 months. The probability of being dead at 2 months was higher (not significant [NS]) in group A (39% +/- 11%) than in group B (18% +/- 9%). The study was stopped by the follow-up committee and the sponsor (Assistance Publique-Hopitaux de Paris). The frequency of severe infections within 2 months was higher in group A than in group B (P <.002). This difference was potentially related to a significantly lower ex vivo stimulation capacity of neutrophils. There were no differences between the two groups in terms of Maddrey scores at any time point. In conclusion, three infusions of 10 mg/kg of infliximab in association with prednisolone may be harmful in patients with severe AAH because of the high prevalence of severe infections.

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Aliment Pharmacol Ther. 2004 Apr 1;19(7):707-14.
Review article: current management of alcoholic liver disease.
Tome S, Lucey MR.
Liver Unit, Internal Medicine Department, Complejo Hospitalario Universitario de Santiago de Compostela, Spain.

Alcoholic liver disease, including acute alcoholic hepatitis and alcoholic cirrhosis, is a major cause of morbidity and mortality in the Western world. Abstinence remains the cornerstone of management of all forms of alcoholic liver disease. Recent research, which has elucidated the mechanisms of alcohol-induced liver injury, offers the prospect of advances in the management of alcoholic liver disease. We review the most recent data on the efficacy of treatment of acute alcoholic injury, including nutritional support, corticosteroids, anti-inflammatory agents and antioxidants, and agents that are directed against the progression to fibrosis, such as colchicines, propylthiouracil and antioxidants. Although these therapies offer a tantalizing glimpse into a future that may include therapies that directly alter the process of injury and repair in the liver, none has been shown consistently to improve the course of alcoholic liver damage. Consequently, liver transplantation remains an ultimate option for selected patients with liver failure due to chronic alcoholic liver damage.

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Am J Gastroenterol. 2004 Feb;99(2):255-60.
A pilot study of the safety and tolerability of etanercept in patients with alcoholic hepatitis.
Menon KV, Stadheim L, Kamath PS, Wiesner RH, Gores GJ, Peine CJ, Shah V.
Advanced Liver Disease Study Group, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.

BACKGROUND: Alcoholic hepatitis is a cause of major morbidity and mortality, and effective therapeutic regimens to treat this condition are lacking. Both experimental and clinical evidence indicates that tumor necrosis factor alpha (TNF), and the downstream cytokine interleukin-6 (IL-6), correlate with disease severity and may contribute to the pathogenesis and clinical sequelae of alcoholic hepatitis, thereby implicating a possible role for inhibition of TNF in the treatment of alcoholic hepatitis. OBJECTIVE: The aim of the current study was to assess the safety and tolerability of a p75-soluble TNF receptor:FC fusion protein (etanercept), an agent that binds and neutralizes soluble TNF in patients with alcoholic hepatitis in the form of an open-label pilot trial. METHODS: Etanercept administration was targeted for 2 wk duration in 13 patients with moderate or severe alcoholic hepatitis as assessed by a discriminant function value greater than 15 and/or the presence of spontaneous hepatic encephalopathy. RESULTS: CONCLUSIONS: On an intention-to-treat basis, the 30-day survival rate of patients receiving etanercept was 92% (12/13). Adverse events that were encountered included infection, hepatorenal decompensation, and GI bleeding, which required premature discontinuation of etanercept in 23% of patients (3/13). This is the first study to examine TNF inhibition with etanercept in patients with alcoholic hepatitis and the results of this study support the rationale for larger controlled studies to further assess safety and efficacy.

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Eur J Gastroenterol Hepatol. 2004 Jan;16(1):9-18.
Ten years' follow-up of 472 patients following transjugular intrahepatic portosystemic stent-shunt insertion at a single centre.
Tripathi D, Helmy A, Macbeth K, Balata S, Lui HF, Stanley AJ, Redhead DN, Hayes PC.
Liver Unit, The Royal Infirmary, Edinburgh, UK. d.tripathi@ed.ac.uk

BACKGROUND: Transjugular intrahepatic portosystemic stent-shunt (TIPSS) is increasingly used for the management of portal hypertension. We report on 10 years' experience at a single centre. METHODS: Data held in a dedicated database was retrieved on 497 patients referred for TIPSS. The efficacy of TIPSS and its complications were assessed. RESULTS: Most patients were male (59.4%) with alcoholic liver disease (63.6%), and bleeding varices (86.8%). Technical success was achieved in 474 (95.4%) patients. A total of 13.4% of patients bled at portal pressure gradients < or = 12 mmHg, principally from gastric and ectopic varices. Procedure-related mortality was 1.2%. The mean follow-up period of surviving patients was 33.3 +/- 1.9 months. Primary shunt patency rates were 45.4% and 26.0% at 1 and 2 years, respectively, while the overall secondary assisted patency rate was 72.2%. Variceal rebleeding rate was 13.7%, with all episodes occurring within 2 years of TIPSS insertion, and almost all due to shunt dysfunction. The overall mortality rate was 60.4%, mainly resulting from end-stage liver failure (42.5%). Patients who bled from gastric varices had lower mortality than those from oesophageal varices (53.9% versus 61.5%, P < 0.01). The overall rate of hepatic encephalopathy was 29.9% (de novo encephalopathy was 11.5%), with pre-TIPSS encephalopathy being an independent predicting variable. Refractory ascites responded to TIPSS in 72% of cases, although the incidence of encephalopathy was high in this group (36.0%). CONCLUSIONS: TIPSS is effective in the management of variceal bleeding, and has a low complication rate. With surveillance, good patency can be achieved. Careful selection of patients is needed to reduce the encephalopathy rate.

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Aliment Pharmacol Ther. 2004 Apr;19(7):707-14.
Current management of alcoholic liver disease.
Tome S, Lucey MR.
Liver Unit, Internal Medicine Department, Complejo Hospitalario Universitario de Santiago de Compostela, Spain.

Summary Alcoholic liver disease, including acute alcoholic hepatitis and alcoholic cirrhosis, is a major cause of morbidity and mortality in the Western world. Abstinence remains the cornerstone of management of all forms of alcoholic liver disease. Recent research, which has elucidated the mechanisms of alcohol-induced liver injury, offers the prospect of advances in the management of alcoholic liver disease. We review the most recent data on the efficacy of treatment of acute alcoholic injury, including nutritional support, corticosteroids, anti-inflammatory agents and antioxidants, and agents that are directed against the progression to fibrosis, such as colchicines, propylthiouracil and antioxidants. Although these therapies offer a tantalizing glimpse into a future that may include therapies that directly alter the process of injury and repair in the liver, none has been shown consistently to improve the course of alcoholic liver damage. Consequently, liver transplantation remains an ultimate option for selected patients with liver failure due to chronic alcoholic liver damage.

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Rev Esp Enferm Dig. 2004 Jan;96(1):60-73.
Diagnostic and therapeutic approach to cholestatic liver disease.
[Article in English, Spanish]
Perez Fernandez T, Lopez Serrano P, Tomas E, Gutierrez ML, Lledo JL, Cacho G, Santander C, Fernandez Rodriguez CM.
Unit of Digestive Diseases, Fundacion Hospital Alcorcon, Madrid, Spain.

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some specific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hyperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a middle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, alpha1-antitrypsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.

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Ann Surg. 2004 Jan;239(1):93-8.
Societal reintegration after liver transplantation: findings in alcohol-related and non-alcohol-related transplant recipients.
Cowling T, Jennings LW, Goldstein RM, Sanchez EQ, Chinnakotla S, Klintmalm GB, Levy MF.
Transplantation Services, Baylor University Medical Center, Dallas, TX 76104, USA.

OBJECTIVE: To compare the degree of societal reintegration between alcohol-related and non-alcohol-related liver transplant recipients. SUMMARY BACKGROUND DATA: Orthotopic liver transplantation (OLTX) is the treatment of choice for end-stage liver disease of various etiologies. Returning patients to society to lead active and productive lives is a key goal of OLTX. METHODS: A questionnaire assessing societal reintegration was administered by phone to 84 alcoholic liver disease (ALD) OLTX recipients (ALDs) and 68 non-ALD OLTX recipients having undergone OLTX at a single-center urban not-for-profit teaching hospital. Sixty-eight non-ALD OLTX recipients, serving as the control group (Controls), were matched to the ALDs by age, sex, and length of follow-up. Participation levels were assessed in the following areas: employment, homemaking, academic study, support of others through financial and/or care-giving efforts, and involvement in social or community groups and activities. RESULTS: Seventy-nine percent of ALDs and 81% of Controls were male. Median age was 53 years for ALDs and 54 years for Controls. Median length of follow-up for both groups separately was 52 months. No significant differences were noted between ALDs and Controls in the proportion of employed individuals, homemakers, students, and supporters of others. Controls were significantly more likely than ALDs to be involved in structured social activities and routine volunteer work. CONCLUSIONS: Alcohol-related and non-alcohol-related OLTX recipients appear to return to society to lead similarly active and productive lives. ALD OLTX recipients appear less likely to be involved in structured social activities and routine volunteer work than non-ALD OLTX recipients.

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J Gastroenterol Hepatol. 2003 Dec;18(12):1332-44.
Pathogenesis and management of alcoholic hepatitis.
Haber PS, Warner R, Seth D, Gorrell MD, McCaughan GW.
Drug Health Services and AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital, and Department of Medicine, University of Sydney, Sydney, Australia. phaber@mail.edu.au

Alcoholic hepatitis is a potentially life-threatening complication of alcoholic abuse, typically presenting with symptoms and signs of hepatitis in the presence of an alcohol use disorder. The definitive diagnosis requires liver biopsy, but this is not generally required. The pathogenesis is uncertain, but relevant factors include metabolism of alcohol to toxic products, oxidant stress, acetaldehyde adducts, the action of endotoxin on Kupffer cells, and impaired hepatic regeneration. Mild alcoholic hepatitis recovers with abstinence and the long-term prognosis is determined by the underlying disorder of alcohol use. Severe alcoholic hepatitis is recognized by a Maddrey discriminant function >32 and is associated with a short-term mortality rate of almost 50%. Primary therapy is abstinence from alcohol and supportive care. Corticosteroids have been shown to be beneficial in a subset of severely ill patients with concomitant hepatic encephalopathy, but their use remains controversial. Pentoxifylline has been shown in one study to improve short-term survival rates. Other pharmacological interventions, including colchicine, propylthiouracil, calcium channel antagonists, and insulin with glucagon infusions, have not been proven to be beneficial. Nutritional supplementation with available high-calorie, high-protein diets is beneficial, but does not improve mortality. Orthotopic liver transplantation is not indicated for patients presenting with alcoholic hepatitis who have been drinking until the time of admission, but may be considered in those who achieve stable abstinence if liver function fails to recover.

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Alcohol Clin Exp Res. 2003 Nov;27(11):1757-64.
I. Veterans Affairs Cooperative Study of Polyenylphosphatidylcholine in Alcoholic Liver Disease: effects on drinking behavior by nurse/physician teams.
Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S; For the Veterans Affairs Cooperative Study 391 Group.
Bronx Veterans Affairs Medical Center and the Mount Sinai School of Medicine, New York 10468, USA. liebercs@aol.com

BACKGROUND: This multicenter prospective, randomized, double-blind placebo-controlled trial was designed to evaluate the effectiveness of polyenylphosphatidylcholine against the progression of liver fibrosis toward cirrhosis in alcoholics. Seven hundred eighty-nine alcoholics with an average intake of 16 drinks per day were enrolled. To control excessive drinking, patients were referred to a standard 12-step-based alcoholism treatment program, but most patients refused to attend. Accordingly, study follow-up procedures incorporated the essential features of the brief-intervention approach. An overall substantial and sustained reduction in drinking was observed. Hepatic histological and other findings are described in a companion article. METHODS: Patients were randomized to receive daily three tablets of either polyenylphosphatidylcholine or placebo. Monthly follow-up visits included an extensive session with a medical nurse along with brief visits with a study physician (hepatologist or gastroenterologist). A detailed physical examination occurred every 6 months. In addition, telephone consultations with the nurse were readily available. All patients had a liver biopsy before entry; a repeat biopsy was scheduled at 24 and 48 months. RESULTS: There was a striking decrease in average daily alcohol intake to approximately 2.5 drinks per day. This was sustained over the course of the trial, lasting from 2 to 6 years. The effect was similar both in early dropouts and long-term patients, i.e., those with a 24-month biopsy or beyond. CONCLUSIONS: In a treatment trial of alcoholic liver fibrosis, a striking reduction in alcohol consumption from 16 to 2.5 daily drinks was achieved with a brief-intervention approach, which consisted of a relative economy of therapeutic efforts that relied mainly on treatment sessions with a medical nurse accompanied by shorter reinforcing visits with a physician. This approach deserves generalization to address the heavy drinking problems commonly encountered in primary care and medical specialty practices.

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Alcohol Clin Exp Res. 2003 Nov;27(11):1765-72.
II. Veterans Affairs Cooperative Study of Polyenylphosphatidylcholine in Alcoholic Liver Disease.
Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S; For the Veterans Affairs Cooperative Study 391 Group.
Bronx Veterans Affairs Medical Center and the Mount Sinai School of Medicine, New York 10468, USA. liebercs@aol.com

BACKGROUND: Polyenylphosphatidylcholine (PPC) has been shown to prevent alcoholic cirrhosis in animals. Our aims were to determine the effectiveness of PPC in preventing or reversing liver fibrosis in heavy drinkers and to assess the extent of liver injury associated with the reduced drinking achieved in these patients. METHODS: This randomized, prospective, double-blind, placebo-controlled clinical trial was conducted in 20 Veterans Affairs Medical Centers with 789 patients (97% male; mean age, 48.8 years) averaging 16 drinks per day (1 drink = 14 g of alcohol) for 19 years. A baseline liver biopsy confirmed the presence of perivenular or septal fibrosis or incomplete cirrhosis. They were randomly assigned either PPC or placebo. Liver biopsy was repeated at 24 months, and the main outcome measure was the stage of fibrosis compared with baseline. Progression was defined as advancing to a more severe stage. RESULTS: The 2-year biopsy was completed in 412 patients. PPC did not differ significantly from placebo in its effect on the main outcome. Alcohol intake was unexpectedly reduced in both groups to approximately 2.5 drinks per day. With this intake, 21.4% advanced at least one stage (22.8% of PPC patients and 20.0% of placebo patients). The hepatitis C virus-positive subgroup exhibited accelerated progression. Improvement in transaminases and bilirubin favoring PPC was seen at some time points in other subgroups (hepatitis C virus-positive drinkers or heavy drinkers). CONCLUSIONS: PPC treatment for 2 years did not affect progression of liver fibrosis. A trend in favor of PPC was seen for transaminases and bilirubin (in subgroups). One of five patients progressed even at moderate levels of drinking, and thus health benefits commonly associated with moderate drinking do not necessarily extend to individuals in the early stages of alcoholic liver disease.

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Neurology. 2003 Nov 11;61(9):1174-8.
Neurologic complications of liver transplantation in adults.
Lewis MB, Howdle PD.
St. James's University Hospital, Leeds, UK. m-k-lewis@msn.com

OBJECTIVE: To describe the incidence and nature of neurologic complications following liver transplantation. METHODS: Adult patients who received liver transplants at St. James's University Hospital between September 1, 1990, and August 31, 2000, were identified. Case notes were reviewed and demographic data, details of the liver disease, neurologic complications, and discharge information were recorded. RESULTS: The authors identified 657 patients and traced the case notes of 627 (95.4%). These patients had a total of 711 transplants. Neurologic complications occurred following 185 transplants (26%) affecting 170 patients (27%). The most common complications were diffuse encephalopathies, which affected 66 patients (11%), and seizures, which affected 37 patients (6%). Forty-three percent of patients with alcoholic liver disease and 41% of patients with primary biliary cirrhosis experienced a neurologic complication. These proportions were higher than for other transplant indications (p < 0.001). Patients who experienced a neurologic problem spent longer in hospital (p < 0.01) and had a poorer outcome (p < 0.001). CONCLUSIONS: Neurologic complications occur following 26% of liver transplants. A higher proportion of patients who received transplants for alcoholic liver disease and primary biliary cirrhosis experienced neurologic complications than those receiving transplants for other reasons. Patients who experience a neurologic problem spend longer in hospital and have a poorer outcome.

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Liver Transpl. 2003 Sep;9(9):921-8.
An evaluation of long-term outcomes after liver transplantation for cryptogenic cirrhosis.
Heneghan MA, Zolfino T, Muiesan P, Portmann BC, Rela M, Heaton ND, O'grady JG.
Institute of Liver Studies, King's College Hospital, Denmark Hill, London, England.

Patients with cryptogenic cirrhosis (CC) comprise a significant proportion of liver transplant recipients. Poor outcome after transplantation has been reported by some centers, with fibrosis occurring in a significant proportion of patients. Outcome of 46 patients with CC who underwent transplantation between 1989 and 1999 at King's College Hospital London were compared with time-matched recipients who underwent transplantation for hepatitis C virus (HCV) cirrhosis (n = 58) and patients with alcohol-related cirrhosis (AC, n = 53) during the same time period. Mean follow-up was 46 +/- 37 months for CC patients, 41 +/- 31 months for AC patients, and 49 +/- 31 months for HCV patients. No protocol liver biopsy specimens were obtained, and biopsies were performed only for investigation of biochemical abnormalities. Acute cellular rejection occurred in 30% of CC, 26% of AC, and 37% of HCV patients (P = NS). Overall patient and graft survival at 1 year was 85% and 80% for CC patients, 87% and 81% for AC patients, and 91% and 82% for patients with HCV (P = NS). Five-year patient and graft survival was 81% and 77% for CC patients, 60% and 48% for AC patients, and 79% and 57% for HCV patients (Log rank; P =.369). Twenty-two percent of CC patients had inflammation on last evaluable liver biopsy, compared with 25% of patients who underwent transplantation for AC and 68% of patients who underwent transplantation for HCV. No patient who underwent transplantation for CC had histologic evidence of cirrhosis on last evaluable biopsy, compared with 2% of patients who underwent transplantation for AC and 16% of patients who underwent transplantation for HCV (Chi-squared = 13.053, P =.0015). These results suggest that CC is a favorable indication for OLT and that although a proportion of patients develop inflammation in the liver allograft, this does not result in significant graft dysfunction or loss.

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Aliment Pharmacol Ther. 2003 Aug 15;18(4):357-73.
Review article: Nutritional therapy in alcoholic liver disease.
Stickel F, Hoehn B, Schuppan D, Seitz HK.
Department of Medicine I, University of Erlangen-Nuremberg, Germany.

Chronic alcohol consumption may lead to primary and secondary malnutrition. In particular, protein energy malnutrition not only aggravates alcoholic liver disease but also correlates with impaired liver function and increased mortality. Therefore, in these patients, adequate nutritional support should be implemented in order to improve their prognosis. Clinical trials addressing this issue have shown that nutritional therapy either enterally or parenterally improves various aspects of malnutrition, and there is increasing evidence that it may also improve survival. Therefore, malnourished alcoholics should be administered a diet rich in carbohydrate- and protein-derived calories preferentially via the oral or enteral route. Micronutrient deficiencies typically encountered in alcoholics, such as for thiamine and folate, require specific supplementation. Patients with hepatic encephalopathy may be treated with branched-chain amino acids in order to achieve a positive nitrogen balance. Fatty liver represents the early stage of alcoholic liver disease, which is usually reversible with abstinence. Metadoxine appears to improve fatty liver but confirmatory studies are necessary. S-adenosyl-L-methionine may be helpful for patients with severe alcoholic liver damage, since various mechanisms of alcohol-related hepatotoxicity are counteracted with this essential methyl group donor, while a recent large trial showed that the use of polyenylphosphatidylcholine is of limited efficacy.

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Liver Transpl. 2003 Jul;9(7):772-5.
First report of a psychosocial intervention for patients with alcohol-related liver disease undergoing
liver transplantation.
Georgiou G, Webb K, Griggs K, Copello A, Neuberger J, Day E.
Addictive Behaviours Centre, Birmingham, England.

Performing transplantations in patients with alcoholic liver disease raises great concerns for both clinicians and lay people, not least because of the fear that relapse back to drinking after the procedure may lead to poor outcomes. Therefore it is important to develop and evaluate new strategies for assessing and supporting such patients. A program of psychosocial intervention was developed to assist patients undergoing transplantation for alcoholic liver disease in coping with their alcohol problems. We describe a feasibility study of its implementation in a group of 20 such patients. This report shows that it is feasible to deliver a time-limited psychological intervention to patients undergoing assessment for liver transplantation. The intervention was readily integrated into the usual transplantation process and was acceptable to both patients and staff. Further research is required to clarify its impact on longer-term outcome measures.

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QJM. 2003 Jun;96(6):391-400.
Recent developments in the treatment of alcoholic hepatitis.
Madhotra R, Gilmore IT.
Milton Keynes General Hospital, Milton Keynes, and. Royal Liverpool University Hospital, Liverpool, UK.

Alcoholic hepatitis is a form of acute injury to liver tissue that is also a precursor of cirrhosis, and carries significant morbidity and mortality. Severe alcoholic hepatitis in particular carries a high short-term mortality, and also places an enormous burden on stretched healthcare resources. Treatment of alcoholic hepatitis has been limited to supportive management and nutritional supplementation without clear improvements in outcome, and the timing and patient selection for hepatic transplantation is problematic. The use of corticosteroids has remained controversial for many years, but probably has a role in selected patients. Various other therapeutic strategies have been tested over the decades and none has shown any consistent benefit. Recently there have been major developments in our understanding of the mechanisms of alcoholic liver injury, including the role of cytokines and hepatocyte apoptosis. For the first time, there are exciting possibilities for specific therapies for this challenging and serious condition.

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Arq Gastroenterol. 2002 Jul-Sep;39(3):147-52. Epub 2003 May 21.
[Outcome of liver transplantation in patients with alcoholic liver disease]
[Article in Portuguese]
Parolin MB, Coelho JC, da Igreja M, Pedroso ML, Groth AK, Goncalves CG.
Servico de Transplante Hepatico, Hospital de Clinicas, Universidade Federal do Parana, Brasil. mbparolin@hotmail.com

BACKGROUND: Liver transplantation is accepted as effective therapeutic option for end-stage liver disease, including alcoholic liver disease AIM: To evaluate the outcome of liver transplantation for alcoholic liver disease in the Liver Transplantation Program at "Hospital de Clinicas" of the Federal University of Parana, Curitiba, PR, Brazil. PATIENTS AND METHODS: It was performed a retrospective study of the patients who underwent liver transplantation for alcoholic end-stage liver disease between September 1991 and January 2001. The minimum abstinence period required was 6 months before liver transplantation. Identification of alcohol consumption after liver transplantation was determinated by information provided by patient or family and biochemical or histological anormalities. RESULTS: Twenty patients underwent liver transplantation for alcoholic liver disease in the study period, 95% (19/20) were men and the median age was 50 years (29-61 years). Seventy-five percent of the patients (15/20) had severe liver disfunction (Child C class) in the pre-transplant period. In six of them (30%) there was association with viral hepatitis and in one, with hepatocarcinoma. Median abstinence period before liver transplantation was 24 months, varying from 9 to 120 months. One-year and 3-year survival rate were 75% and 50%, respectively. The main complications were: acute cellular rejection (40%), chronic rejection (5%), hepatic artery thrombosis (15%), biliary complications (15%), bacterial or fungal infections (45%), cytomegalovirus infection (20%). Three patients returned to alcohol use after liver transplantation CONCLUSION: The survival of patients who received liver transplant for alcoholic cirrhosis are satisfactory. In the present study there was a small index of alcohol use after liver transplantation.

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J Hepatol. 2003 May;38(5):629-34.
Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter?
Pageaux GP, Bismuth M, Perney P, Costes V, Jaber S, Possoz P, Fabre JM, Navarro F, Blanc P, Domergue J, Eledjam JJ, Larrey D.
Federation medico-chirurgicale d' Hepato-gastroenterologie et Transplantation, Hopital Saint Eloi, 80 rue Augustin Fliche, 34295 CHU Cedex 5, Montpellier, France

BACKGROUND/AIMS: The aim of this study was to distinguish the types of alcohol consumption after liver transplantation (LT) for alcoholic cirrhosis and to assess the consequences of heavy drinking.METHODS: Patients transplanted for alcoholic cirrhosis were studied. Alcoholic relapse diagnosis was based upon patient's and family members' reports, liver enzyme tests, graft biopsy, and use of urine alcohol test.RESULTS: One hundred twenty-eight patients were studied, with a mean follow-up of 53.8 months. After LT, 69% of patients were abstinent, 10% were occasional drinkers, and 21% were heavy drinkers. Actuarial survival rates were not different, but three of the seven deaths observed among heavy drinkers were directly related to alcohol relapse. Although there was no difference between the three groups concerning the rejection rates, all rejection episodes observed in the group of heavy drinkers were related to poor compliance with immunosuppressive drugs. One heavy drinker developed alcoholic cirrhosis.CONCLUSIONS: The present study indicates that patients can resume heavy alcohol consumption after LT for alcoholic liver disease (ALD) and their grafts can be injured because of poor compliance with immunosuppressive drugs and alcohol-related liver injury. Although patient survival was not influenced by alcohol relapse, heavy alcohol consumption can be responsible for patients' death.

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Z Gastroenterol. 2003 Apr;41(4):333-42.
[Alcoholic liver disease—established treatment and new therapeutic approaches]
[Article in German]
Stickel F, Seitz HK, Hahn EG, Schuppan D.
Medizinische Klinik I und Poliklinik, Friedrich-Alexander-Universitat Erlangen-Nurnberg, Erlangen. felix.stickel@med1.imed.uni-erlangen.de

Alcoholic liver disease is the most frequent organ damage encountered in chronic alcoholics and the annual death rate attributed to alcohol-induced end-stage liver disease exceeds that of car accidents. Alcoholic liver damage occurs mainly due to the toxicity of its first metabolite acetaldehyde, and due to interactions with numerous macro- and micronutrients. Established treatment options comprise psychotherapy aiming to achieve abstinence, nutritional therapy, management of hepatological complications, and liver transplantation in selected individuals. Since these therapeutic approaches are unsuccessful in many patients, pharmacological therapies of alcoholic liver disease are being investigated. Many drugs failed to be beneficial or have even shown toxicity. However, some agents are promising, such as S-adenosyl-L-methionine (SAMe), pentoxifylline, metadoxin, polyenylphosphatidylcholine or inhibitors of the cytochrome P450 2E1 isoenzyme. In severely ill patients with alcoholic hepatitis, drugs with anti-tumor necrosis factor alpha activity are currently investigated in clinical trials. If and how far corticosteroids are beneficial remains controversial and their use should be restricted to selected patients. Anabolic steroids used to enhance the nutritional status may lead to serious side effects while having a marginal benefit. Silymarin has not been proven efficacious in alcoholic cirrhosis and clinical trials are ongoing which aim to elucidate its therapeutic value in less advanced stages of liver disease.

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Liver Int. 2003;23 Suppl 3:66-72.
Economic evaluation and 1-year survival analysis of MARS in patients with alcoholic liver disease.
Hessel FP, Mitzner SR, Rief J, Guellstorff B, Steiner S, Wasem J.
Institute for Health Care Management, University of Essen, Germany. franz.hessel@uni-essen.de

Objective of this study was to determine 1-year survival, costs and cost-effectiveness of the artificial liver support system Molecular Adsorbent Recirculating System (MARS) in patients with acute-on-chronic liver failure (ACLF) and an underlying alcoholic liver disease. In a case-control study, 13 patients treated with MARS were compared to 23 controls of similar age, sex and severity of disease. Inpatient hospital costs data were extracted from patients' files and hospital's internal costing. Patients and treating GPs were contacted, thus determining resource use and survival 1-year after treatment. Mean 1-year survival time in MARS group was 261 days and 148 days in controls. Kaplan-Meier analysis shows advantages of MARS patients (Logrank: P=0.057). Direct medical costs per patient for initial hospital stay and 1-year follow-up from a payer's perspective were Euro 18,792 for MARS patients and Euro 9638 for controls. The costs per life-year gained are Euro 29,719 (time horizon 1 year). From a societal perspective, the numbers are higher (costs per life-year gained: Euro 79,075), mainly because of the fact that there is no regular reimbursement of MARS and therefore intervention costs were not calculated from payer's perspective. A trade-off between medical benefit and higher costs has to be made, but 1-year results suggest an acceptable cost-effectiveness of MARS. Prolonging the time horizon and including indirect

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Wiad Lek. 2003;56(1-2):61-70
[Alcoholic liver disease]
[Article in Polish]
Waluga M, Hartleb M.
Katedry i Kliniki Gastroenterologii Slaskiej Akademii Medycznej w Katowicach.

Ethanol toxicity on liver is a function of duration of alcoholism, amount of daily intake of alcohol and patient's nutrition. The threshold of alcohol toxicity on the liver is about 40 g of ethanol daily in men and 20-30 g in women, however liver cirrhosis develops in no more than 8-20% of patients exceeding this values. Ethanol is oxidized in the liver to acetaldehyde--a compound considerably more toxic than ethanol itself. Despite small amount of alcohol dehydrogenase (ADH) found in gastric mucosa, the metabolism of ethanol in this site may have an important hepatoprotective effect. The oxidation of ethanol is associated with a change of hepatocyte redox homeostasis, which leads to a number of metabolic disorders such as lactic acidosis, hyperlipidaemia and hyperuricaemia. Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, in particular cytochrome CYP2E1. This fact is responsible for development in alcoholic liver associated with rise of oxygen consumption, excessive production of free radicals and increased metabolism of ethanol, vitamin A and testosterone. Ethanol and acetaldehyde have a deleterious effect, both the direct and indirect, on hepatocytes e.g., generating radical oxygen species and damaging intestinal mucosal barrier. Cellular oxidative stress that is caused by both an excess of free radicals and the antioxidatives' deficiency (glutathion, vitamin E, phosphatidylcholine), may be the principal factor responsible for progression of alcoholic liver disease. Among other factors accelerating alcohol-related liver lesion there are certain drugs, high fat diet, infection with HCV and genetic factors (female sex, enzymatic polymorphic forms of ADH and ALDH, hemochromatosis). Great importance in pathogenesis of necrotic and inflammatory hepatic events is being attributed to portal endotoxaemia and cytokines induced within the liver, in particular TNF-alpha and interleukin 8. These cytokines play a key role in development of alcoholic hepatitis, which clinical severity ranges from subclinical to fatal forms. Apart from abstinence, the treatment of alcohol liver disease is based on hyperalimentation, since alcoholism is generally associated with protein malnutrition. In severe forms of alcohol hepatitis corticosteroids are recommended.

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Hepatology. 2003 Apr;37(4):887-92.
A randomized controlled trial of ursodeoxycholic acid in patients with alcohol-induced
cirrhosis and jaundice.
Pelletier G, Roulot D, Davion T, Masliah C, Causse X, Oberti F, Raabe JJ, Van Lemmens C, Labadie H, Serfaty L; URSOMAF Group.
Department of Gastroenterology of Hopital Bicetre, Assistance Publique-Hoopitaux de Paris, Paris, France.

The aim of our multicenter study was to assess the efficacy of ursodeoxycholic acid (UDCA) on the survival of patients with alcohol-induced cirrhosis and jaundice. We included patients with histologically proven alcohol-induced cirrhosis and serum bilirubin >50 micromol/L. After randomization, patients received either UDCA (13-15 mg/kg/d) or a placebo for 6 months. Two hundred twenty-six patients (113 in each group) were included in 24 centers. There were 139 men and 87 women, mean age of 50.3 years. Seventy-four percent had associated alcohol-induced hepatitis, and 24% received a corticosteroid therapy. At inclusion, the 2 groups were comparable for the main clinical and biologic parameters, but serum bilirubin was higher in the UDCA group than in the placebo group (163 micromol/L vs. 145 micromol/L, P <.03). The percentage of patients lost at follow-up or who resumed their alcoholism during the study was comparable in the 2 groups. During the study, 55 patients died, 35 in the UDCA group and 20 in the placebo group. In the intention to treat analysis, the probability of survival at 6 months (Kaplan-Meier method) was lower in the UDCA than in the P group (69% vs. 82%, respectively; P =.04, log-rank test). After adjustment on the bilirubin level at entry (Cox model), the independent predictive value of the treatment group did not reach the statistical level (RR = 1.64, CI 0.85-2.85; P =.077). In conclusion, UDCA administered at the dose recommended in primary biliary cirrhosis has no beneficial effect on the 6-month survival of patients with severe alcohol-induced cirrhosis. An inappropriate dosage of UDCA cannot be excluded as an explanation for the lack of therapeutic benefit.

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Gastroenterology. 2003 Mar;124(3):778-90.
Oxidants and antioxidants in alcohol-induced liver disease.
Arteel GE.
Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, Kentucky, USA. gavin.arteel@lousville.edu

Although there are numerous experimental data indicating that oxidative stress plays a role in the initiation and progression of alcohol-induced liver disease (ALD), this work has yet to translate into an accepted antioxidant therapy for ALD in humans. With a better understanding of the mechanisms by which oxidative stress leads to liver damage during alcohol exposure, therapies that are more targeted at the cellular/molecular level may be applied in the clinic with potentially greater success. This article discusses the general concepts of oxidative stress and how it relates to current hypotheses in alcohol-induced liver injury, as well as lists several key questions that remain to be addressed in this field: (1) Which prooxidants are involved in ALD? (2) What are the sources of prooxidants in the liver during alcohol exposure? (3) How are oxidants involved in alcohol-induced liver injury? (4) Can a rational and effective antioxidant therapy against ALD be developed?

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Cochrane Database Syst Rev. 2003;(1):CD003045.
Anabolic-androgenic steroids for alcoholic liver disease.
Rambaldi A, Iaquinto G, Gluud C.
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshopitalet, Blegdamsvej 9, Department 7201, Copenhagen, Denmark, DK-2100. arambaldi@hotmail.com

BACKGROUND: Alcohol is one of the most common causes of liver disease in the Western World today. Randomised clinical trials have examined the effects of anabolic-androgenic steroids for alcoholic liver disease. OBJECTIVES: The objectives were to assess the beneficial and harmful effects of anabolic-androgenic steroids for patients with alcoholic liver disease based on the results of randomised clinical trials. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE, EMBASE, and full text searches were combined (all searched December 2001). Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Only randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included. Interventions encompassed anabolic-androgenic steroids at any dose or duration versus placebo or no intervention. The trials could be double blind, single blind, or unblinded. The trials could be unpublished or published and no language limitations were applied. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method. The statistical package (RevMan and MetaView) provided by the Cochrane Collaboration was used. The methodological quality of the randomised clinical trials was evaluated by components of methodological quality. MAIN RESULTS: Combining the results of five randomised clinical trials randomising 499 patients with alcoholic hepatitis and/or cirrhosis demonstrated no significant effects of anabolic-androgenic steroids on mortality (relative risk (RR) 0.96, 95% confidence interval (CI) 0.72 to 1.28), liver related mortality (RR 0.83, 95% CI 0.60 to 1.15), complications of liver disease (RR 1.25, 95% CI 0.74 to 2.10), and liver histology. Further, anabolic-androgenic steroids did not significantly affect a number of other outcome measures. Anabolic-androgenic steroids were not associated with a significantly increased risk of non-serious adverse events but with the seldom occurrence of serious adverse events (RR 4.54, 95% CI 0.57 to 36.30). REVIEWER'S CONCLUSIONS: This systematic review could not demonstrate any significant beneficial effects of anabolic-androgenic steroids on any clinically important outcomes (mortality, liver related mortality, liver complications, and histology) of patients with alcoholic liver disease.

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Clin Ter. 2002 Sep-Oct;153(5):305-7.
[Use of ursodeoxycholic acid combined with silymarin in the treatment of chronic ethyl-toxic hepatopathy]
[Article in Italian]
Bettini R, Gorini M.
Ospedale di Circolo, Universita degli Studi dell'Insubria, Varese, Italia.

30 patients, affected by chronic ethylic hepatopathy, were treated with 450 mg/daily of ursodeoxycholic acid (UDCA): after six months, a significant decrease of serum hepatic enzymes was noted. The addition of silymarin (400 mg/daily) to UDCA in other 30 patients, induced a further improvement of hepatic function.

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J Ethnopharmacol. 2003 Jan;84(1):47-50.
Liv.52 in alcoholic liver disease: a prospective, controlled trial.
de Silva HA, Saparamadu PA, Thabrew MI, Pathmeswaran A, Fonseka MM, de Silva HJ.
Department of Pharmacology, Faculty of Medicine, University of Kelaniya, PO Box 6, Thalagolla Road, Ragama, Sri Lanka. asitades@hotmail.com

Liv.52, a hepatoprotective agent of herbal origin, is used empirically for the treatment of alcoholic liver disease in Sri Lanka. We conducted a controlled trial to assess the efficacy of Liv.52 in patients with alcoholic liver disease. Patients with evidence of alcoholic liver disease attending outpatient clinics were included in a prospective, double blind, randomized, placebo controlled trial. During the trial period, 80 patients who fulfilled inclusion criteria were randomly assigned Liv.52 (cases; n = 40) or placebo (controls) the recommended dose of three capsules twice daily for 6 months. All patients underwent clinical examination (for which a clinical score was computed), and laboratory investigations for routine blood chemistry and liver function before commencement of therapy (baseline). Thereafter, clinical assessments were done monthly for 6 months, while laboratory investigations were done after 1 and 6 months of therapy. There was no significant difference in the age composition, alcohol intake and baseline liver function between the two groups. The two-sample t-test was used to analyze data obtained after 1 and 6 months of therapy against baseline values. There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point. There were no reports of adverse effects attributable to the drug. Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease. Copyright 2002 Elsevier Science Ireland Ltd.

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Eksp Klin Gastroenterol. 2002;(5):77-8, 129.
[Pathogenetic therapy of alcoholic liver disease]
[Article in Russian]
Volchkova EV.
I.M. Sechenov Moscow Medical Academy.

Ademetionine (Geptral) can be recommended both for reducing acute attacks of alcoholic hepatitis and for a supporting therapy in patients with chronic liver lesions of the toxic genesis, taking into account its vast positive effect on the liver.

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Liver. 2002;22 Suppl 2:63-8.
Emerging indications for MARS dialysis.
Schachschal G, Morgera S, Kupferling S, Neumayer HH, Lochs H, Schmidt HH.
Charite (CCM), Medzinische Klinik mit Schwerpunkt fur Gastroenterologie und Hepatology, Medzinische Fakultat der Humboldt-Universitat zu Berlin, Germany. schachschal@web.de

MARS stands for Molecular Adsorbent Recirculating System and represents an interesting option in treating patients with liver disease. There is still little known about the best time point of initiating this treatment and the exact selection criteria for patients who may benefit from this therapy. The list of potential applications using this procedure is expanding. We report on the experience in seven patients being treated with MARS dialysis for chronic cholestatic liver disease and acute on chronic liver failure. From August 2000 to October 2001 seven patients received 27 MARS treatments in our clinic, ranging from 2 to 12 treatments per subject. Presented cases were diagnosed as steatohepatitis because of alcoholism (n = 3), vanishing bile duct disease (n = 1), metabolic liver disease (n = 1), primary biliary cirrhosis (n = 1) and drug-induced hepatitis (n = 1). Based on this experience, we discuss the ongoing questions of various indications and the decision to initiate MARS dialysis.

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Alcohol. 2002 Jul;27(3):151-4.
Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease: introduction and
summary of the symposium.
Purohit V, Russo D.
Biomedical Research Branch/Division of Basic Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 6000 Executive Boulevard, Suite 402, Bethesda, MD 20892-7003, USA. vpurohit@willco.niaaa.nih.gov

The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of S-Adenosyl-L-Methionine (SAMe) in the Treatment of Alcoholic Liver Disease" in Bethesda, Maryland, September 2001. Alcoholic liver disease (ALD) is a major cause of illness and death in the United States. Oxidant stress plays a key role in pathogenesis of liver disease. S-Adenosyl-L-methionine, a dietary supplement, is the methyl donor for biochemical methylation reactions and a precursor of glutathione, the main hepatocellular antioxidant. S-Adenosyl-L-methionine has been shown to attenuate liver injury caused by alcohol and other hepatotoxins in some animal models. Understanding the mechanisms by which SAMe attenuates liver injury caused by alcohol may provide useful information for full-scale human clinical trials. For this symposium, seven speakers were invited to address the following issues: (1) impaired methionine metabolism in alcoholic liver injury; (2) regulation of liver function by SAMe; (3) folate deficiency, methionine metabolism, and alcoholic liver injury; (4) attenuating effect of SAMe on ALD in experimental animals; (5) SAMe and mitochondrial glutathione depletion in ALD; (6) SAMe and cytokine production in liver injury; and (7) role of SAMe in the prevention of hepatocarcinogenesis. The presentations of this symposium support the suggestion that SAMe may have potential to treat ALD by (1) acting as a precursor of antioxidant glutathione, (2) repairing mitochondrial glutathione transport system, (3) attenuating toxic effects of proinflammatory cytokines, and (4) increasing DNA methylation. Further studies are required to evaluate the safety and effectiveness of SAMe treatment.

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Ir Med J. 2002 Apr;95(4):108-9, 111.
Severe acute alcoholic hepatitis: an audit of medical treatment.
O'Keefee C, McCormick PA.
Liver Unit, St Vincent's University Hospital, Dublin, Ireland.

Despite advances in treatment, severe alcoholic hepatitis is still associated with a high mortality rate of 30% to 40%. Nutritional support and steroids in selected patients are believed to improve prognosis. In controlled trials steroids have been beneficial in patients with a discriminant function (DF) value >32 or spontaneous hepatic encephalopathy. The aim of this study was to investigate current practice and outcomes in the treatment of acute alcoholic hepatitis. We retrospectively studied patients admitted to our unit with acute alcoholic hepatitis over a 4 year period. Forty-three patients with acute alcoholic hepatitis were admitted between 1994 and 1997. Overall mortality was 26% (11/43). Only 5 patients were treated with steroids of whom 1 died (mortality 20%). Liver biopsy was available in 19/43 of whom 12/19 (63%) had underlying cirrhosis in addition to alcoholic hepatitis. Mortality was higher in patients with a discriminant function of greater than 32 but not significantly so (32%: 8/25 vs 17%: 3/18 p = 0.31). A discriminant function of greater than 32 and contra-indications to steroid use was the best predictor of mortality (60% 6/10 P = 0.0096) compared to patients not fulfilling these criteria In this study overall mortality was comparable with published reports. Of interest was the relatively low liver biopsy rate and the fact that steroids were used in only a minority of eligible patients. We found that mortality was concentrated in a subgroup of patients with a discriminant function value >32 and contra-indications to steroids. These criteria appear to identify a high-risk subgroup of patients. If confirmed, experimental treatments need to be targeted at this group to improve the overall prognosis of acute alcoholic hepatitis.

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Cochrane Database Syst Rev. 2002;(2):CD002800.
Propylthiouracil for alcoholic liver disease.
Rambaldi A, Gluud C.
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, H:S Rigshopitalet, Blegdamsvej 9, Copenhagen, Denmark, DK-2100. arambaldi@hotmail.com

BACKGROUND: Alcohol is the most common cause of liver disease in the Western world today. Randomised clinical trials have addressed the question whether propylthiouracil has any efficacy in patients with alcoholic liver disease. OBJECTIVES: The objectives were to assess the efficacy of propylthiouracil on mortality, clinical symptoms and complications, liver biochemistry, and liver histology in patients with alcoholic liver disease. Adverse events were also analysed. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register (searched July 2001), The Cochrane Controlled Trials Register (Cochrane Library Issue 3, 2001), MEDLINE (January 1966 to July 2001), EMBASE (January 1985 to July 2001) were searched. These electronic searches were combined with full text searches. Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: Randomised clinical trials studying patients with alcoholic steatosis, alcoholic fibrosis, alcoholic hepatitis, and/or alcoholic cirrhosis were included. Interventions encompassed propylthiouracil at any dose versus placebo or no intervention. The trials could be double-blind, single-blind, or unblinded. The trials could be unpublished or published as an article, an abstract, or a letter and no language limitations were applied. DATA COLLECTION AND ANALYSIS: All analyses were performed according to the intention-to-treat method. The statistical package (RevMan and MetaView) provided by the Cochrane Collaboration was used. The methodological quality of the randomised clinical trials was evaluated by components of quality and the Jadad-scale. MAIN RESULTS: Combining the results of six randomised clinical trials including 710 patients demonstrated no significant effects of propylthiouracil versus placebo on mortality (Peto odds ratio (OR) 0.91, 95% confidence interval (CI) 0.59 to 1.40), liver related mortality (OR 0.78, 95% CI 0.45 to 1.33), complications of the liver disease (OR 1.14, 95% CI 0.58 to 2.24), or liver histology. Propylthiouracil was associated with a non significant trend towards an increased risk of non-serious adverse events (OR 1.49, 95% CI 0.74 to 2.99) and with the seldom occurrence of serious adverse events (leukopenia). REVIEWER'S CONCLUSIONS: This systematic review could not demonstrate any significant efficacy of propylthiouracil on any clinically important outcomes (mortality, liver related mortality, liver complications, and liver histology) of patients with alcoholic liver disease and propylthiouracil was associated with adverse events. Accordingly, there is no evidence for using propylthiouracil for alcoholic liver disease outside randomised clinical trials.

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Alcohol Clin Exp Res 2002 May;26(5):731-6
Pathogenesis of alcoholic liver disease—recent advances.
Nanji AA, Su GL, Laposata M, French SW.
Department of Pathology and Center for the Study of Liver Diseases, The University of Hong Kong and Queen Mary Hospital. ananji@pathology.hku.hk

The article summarizes the proceedings of a symposium on recent advances in research on the pathogenesis of alcoholic liver disease at the 2001 RSA meeting in Montreal, Canada. The chairs were Amin A. Nanji and Samuel W. French. The presentations were (1) Role of inflammatory mediators in alcoholic liver injury by Amin A. Nanji, (2) Role of endotoxin, lipopolysaccharide binding protein, CD14 and Toll receptors in alcoholic liver injury by Grace Su, (3) Fatty acid ethyl esters: toxicity, metabolism and markers of ethanol intake by Michael Laposata, and (4) Cyclic changes in gene expression when rats are fed alcohol at a constant rate by Samuel W. French.

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Alcohol 2002 May;27(1):7-11
Liver disease in alcohol abusers. clinical perspective.
Diehl AM.
The Johns Hopkins University, 912 Ross Building, 720 Rutland Street, 21205, Baltimore, MD, USA

Alcoholic liver disease remains one of the most common causes of chronic liver disease in the world. The severity of liver damage related to alcohol varies among different individuals and even within any given individual at different times. Certain symptoms, signs, and abnormal findings on laboratory tests help clinicians distinguish among the various stages of alcohol-induced liver damage and, thus, have some prognostic significance. However, because all stages of this disease can persist for decades without causing overt evidence of serious liver damage, liver biopsy is the only test that can reliably distinguish among the various stages of alcohol-induced liver damage in many patients. The therapy of alcohol-induced liver disease varies according to the severity of histologic liver damage and clinically overt portal hypertension and hepatic dysfunction. Abstinence from alcohol consumption improves the clinical outcome of all stages of alcoholic liver disease. However, only two agents have proved to lessen early mortality in patients who require hospitalization for acutely decompensated alcoholic liver disease. It is not known whether either of these agents or other treatments prevent the development of alcohol-induced cirrhosis or improve the survival of patients who have already developed cirrhosis.

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Int J Surg Pathol 2002 Apr;10(2):115-22
Liver transplantation for alcoholic liver disease with or without hepatitis C.
Goldar-Najafi A, Gordon FD, Lewis WD, Pomfret E, Pomposelli JJ, Jenkins RL, Khettry U.
Department of Pathology, Beth Israel Deaconess Medical Center & Harvard Medical School, Boston MA, USA.

Alcoholic cirrhosis with or without hepatitis C is a common indication for liver transplantation (LT). Comparative post-LT data for the 2 groups are not available. Our aim is to compare the clinicopathologic features of patients with alcoholic liver disease (ETOH) and ETOH/HCV at the time of and after LT and to determine the impact of concomitant hepatitis C virus (HCV) on ETOH patients undergoing LT. A comparative clinical and pathologic analysis at LT and after LT was performed for 56 patients with ETOH and 32 patients with ETOH/HCV. All 88 had cirrhosis at LT. Other native liver features for ETOH and ETOH/HCV, respectively, were: >2+ inflammation 50/56 and 26/32, Mallory's hyalin 12/56 and 6/32, steatosis 9/56 and 7/32, large cell dysplasia 12/56 and 6/32, hepatoma 4/56 and 4/32, iron deposition 24/56 and 12/32; none was statistically significant. The post-LT findings for ETOH and ETOH/HCV were as follows: 1-year survival 93% and 97%; alive 36/56 (419-4,348 days) and 27/32 (488-5,516 days); deaths 20/56 and 5/32; ETOH recurrence 5/56 (all alive) and 3/32 (1 dead); post-LT HCV 4/56 (acquired) and 22/32 (recurrent). Native liver histology in ETOH and ETOH/HCV patients was similar. Post-LT HCV recurrence was common (69%) in ETOH/HCV patients but resulted in death in only 6%. Post-LT ETOH recurrence was uncommon (9%) and progression to liver failure was rare (1.1%). Post-LT outcome for ETOH was excellent, and concomitant HCV did not affect survival.

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Free Radic Biol Med 2002 Mar 15;32(6):487-91
Role of mitochondria in alcoholic liver injury.
Adachi M, Ishii H.
Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.

Oxidative stress and oxygen-derived free radicals are well known to play an important role in the pathogenesis of ethanol-associated liver injury. Active oxidants produced during ethanol metabolism induce mitochondrial membrane depolarization and permeability changes in cultured hepatocytes. These mitochondrial alterations (loss of DeltaPsim and mitochondrial permeability transition [MPT]) are now recognized as a key step in apoptosis. In recent studies, including ours, the MPT has been identified as a key step for the induction of mitochondrial cytochrome c release and caspase activation by ethanol. In addition, chronic and/or acute ethanol modulates intracellular, especially mitochondrial, antioxidant levels, leading to the increased susceptibility to alcoholic liver injury induced by several apoptotic stimuli. In this review, we address the mechanism of mitochondrial alterations and liver injury induced by ethanol.

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J Ayub Med Coll Abbottabad 2001 Jul-Sep;13(3):19-21
Metabolic effects of alcoholism and its relationship with alcoholic liver disease.
Tabassum F, Khurshid R, Karim S, Akhtar MS.
Department of Chemistry, University of Punjab, Lahore.

BACKGROUND: Chronic and excessive ethanol consumption is associated with cellular proliferation, fibrosis, cirrhosis and cancer of liver. It was planned to study the effect of alcohol on different biochemical parameters as distribution of these parameters may lead to several complications in gastrointestinal tract, liver, kidney, brain etc. METHODS: 50 alcoholic males and 20 normal subject (with no history of alcohol) with an age ranges 30-45 years were included in the study. Biochemical parameters related to liver were estimated by standard kit. Besides, ions and electrolytes were also determined by standard kit and flame photometry. RESULTS: It was observed that level of alkaline phosphatase, alanine transferase, protein and globulin were significantly increased as compared to normal subjects. Besides, ions like calcium and phosphate were significantly decreased. On the other hand the level of potassium and magnesium was significantly decreased as compared to normal subjects. Electrophoresis shows a protein of 100 Kda is present in the patients sample as compared to control subjects. CONCLUSION: It is therefore concluded that abnormal biochemical function of liver in alcoholism can lead to several complications, hence further research is needed to reach a definite conclusion.

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Hepatology 2002 Mar;35(3):635-8
Risk factors of fibrosis in alcohol-induced liver disease.
Raynard B, Balian A, Fallik D, Capron F, Bedossa P, Chaput JC, Naveau S.
Service d'Hepato-Gastroenterologie, Hopital Antoine Beclere, 157 rue de la Porte de Trivaux, 92141 Clamart Cedex, France.

In patients with nonalcoholic steatohepatitis (NASH), age, obesity, and diabetes mellitus are independent predictors of the degree of fibrosis. The relative risk for fibrosis adjusted for sex was also associated with increasing grade of Perls stain. The aim of this study was to determine whether the risk factors for fibrosis described in NASH are also risk factors in alcohol-induced liver disease. A total of 268 alcoholic patients with negative hepatitis B virus and hepatitis C virus serology underwent liver biopsy. Fibrosis was assessed semiquantitatively by a score fluctuating between 0 to 8. Liver iron overload was assessed by Perls staining and graded in 4 classes. We have used multivariate regression with partial correlation analysis to assess the variability of fibrosis score according to the value of 7 variables: sex, age, body mass index (BMI) in the past year before the hospitalization when the patient was asymptomatic, daily alcohol intake over the past 5 years, total duration of alcohol abuse, Perls grade, and blood glucose level. In the multivariate regression, fibrosis score was positively correlated with age (P =.001), BMI (P =.002), female sex (P <.05), Perls grade (P <.05), and blood glucose level (P <.05). Twenty percent of the variability of fibrosis score was explained by the 7 variables. In conclusion, after adjustment for daily alcohol intake and total duration of alcohol abuse, BMI, Perls grade, and blood glucose are also independent risk factors for fibrosis in alcohol-induced liver disease, raising therapeutic implications for the management of these patients.

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Alcohol Clin Exp Res 2002 Nov;26(11):1692-6
Serum ubiquitin-protein conjugates in normal subjects and patients with alcoholic liver diseases: immunoaffinity isolation and electrophoretic mobility.
Takagi M, Yamauchi M, Takada And K, Ohkawa K.

BACKGROUND We previously reported that levels of multiubiquitin chains, representing ubiquitin-protein conjugates, were significantly higher in sera of patients with alcoholic liver cirrhosis than in normal subjects and patients with other types of alcoholic liver disease.METHODS To characterize them, ubiquitin-immunoreactive proteins were purified from sera of healthy human volunteers and patients with alcoholic liver diseases by using affinity chromatography on a Sepharose column containing an immobilized monoclonal antibody recognizing conjugated ubiquitin.RESULTS SDS-PAGE analysis followed by Western blotting revealed that the immunoaffinity-purified proteins mainly contained multiple components with molecular masses greater than 60 kDa, almost all of which were immunostained with the ubiquitin antibody. This size heterogeneity was in agreement with the property of ubiquitin-protein conjugates in all cells examined. These results indicate that the immunoaffinity-purified serum proteins are polyubiquitinated proteins presumably derived from some somatic cells. These ubiquitinated proteins obtained from the alcoholic cirrhosis patients were stained more strongly than those from the normal subjects and patients with other types of alcoholic liver disease, although equal amounts of multiubiquitin chains were analyzed simultaneously. In addition, marked differences were observed in the two-dimensional PAGE pattern of the ubiquitin-protein conjugates purified from the alcoholic cirrhosis patient serum compared with those from the normal human serum: four distinct broad spots (presumably polyubiquitin-protein complexes) were observed only in the former.CONCLUSIONS This is the first report on isolation of ubiquitin-protein conjugates from human serum, and it indicates that not only their levels, but also their molecular compositions, were greatly affected by alcoholic cirrhosis.

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Alcohol 2002 Jul;27(3):185
S-Adenosylmethionine, cytokines, and alcoholic liver disease.
McClain C, Hill D, Song Z, Chawla R, Watson W, Chen T, Barve S.
Department of Medicine, University of Louisville Medical Center, 40292, Louisville, KY, USA

Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity. Subnormal AdoMet, elevated serum tumor necrosis factor (TNF), and endotoxemia (LPS) are hallmarks of ALD and experimental liver injury. AdoMet deficiency is attributed to its subnormal synthesis, but mechanisms for increased TNF are not known. AdoMet deficiency may affect the critical balance of proinflammatory (e.g., TNF) and antiinflammatory [e.g., interleukin (IL)-10] cytokines. Rats maintained on a choline-deficient diet with limited amounts of methionine (MCD diet) developed AdoMet deficiency. When challenged with LPS, rats fed MCD diet had significantly increased serum TNF levels and worse liver injury compared with findings for controls. Exogenous AdoMet attenuated liver injury and serum TNF levels. Results of in vitro studies with the use of RAW 264.7 cells demonstrated that exogenous AdoMet supplementation lowered LPS-induced TNF formation in a dose-dependent manner, and AdoMet deficiency enhanced TNF secretion and TNF gene expression. AdoMet also dose-dependently decreased LPS-stimulated TNF production from monocytes obtained from patients with alcoholic hepatitis. Finally, AdoMet supplementation stimulated production of the antiinflammatory cytokine IL-10. Interleukin-10 plays a critical role in the modulation of TNF production, and IL-10 may inhibit hepatic fibrosis. This article will review (1) the role of AdoMet in ALD/liver injury, (2) the role of TNF/proinflammatory cytokines in ALD, (3) potential roles of AdoMet in TNF/proinflammatory cytokine regulation in ALD, and (4) conclusions and future directions.

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Alcohol 2002 Jul;27(3):169
Folate deficiency, methionine metabolism, and alcoholic liver disease.
Halsted C, Villanueva J, Devlin A.
University of California, Davis, 95616, Davis, CA, USA

Methionine metabolism is regulated by folate, and both folate deficiency and abnormal hepatic methionine metabolism are recognized features of alcoholic liver disease (ALD). Previously, histological features of ALD were induced in castrated male micropigs fed diets containing ethanol at 40% of kilocalories for 12 months, whereas in male micropigs fed the same diets for 12 months abnormal methionine metabolism and hepatocellular apoptosis developed. Folate deficiency may promote the development of ALD by accentuating abnormal methionine metabolism. Intact male micropigs received eucaloric diets that were folate sufficient, folate deficient, or each containing 40% of kilocalories as ethanol for 14 weeks. Folate deficiency alone reduced hepatic folates by one half, and ethanol feeding alone reduced methionine synthase, S-adenosylmethionine (SAM), and glutathione (GSH) levels and elevated plasma malondialdehyde (MDA) levels. The combined regimen elevated plasma homocysteine, hepatic S-adenosylhomocysteine (SAH), urinary 8-hydroxy-2-deoxyguanosine (oxy(8)dG), an index of DNA oxidation, and serum aspartate aminotransferase (AST) levels. Terminal hepatic histopathologic characteristics included typical features of steatonecrosis and focal inflammation in pigs fed the combined diet, with no changes in the other groups. Hepatic SAM levels correlated with those of GSH, whereas urinary oxy(8)dG and plasma MDA levels correlated with the SAM:SAH ratio and to hepatic GSH. The results demonstrate the linkage of abnormal methionine metabolism to products of DNA and lipid oxidation and to liver injury. The finding of steatonecrosis and focal inflammation only in the combined diet group supports the suggestion that folate deficiency promotes and folate sufficiency protects against the early onset of methionine cycle-mediated ALD.

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Alcohol 2002 Jul;27(3):155
Role of abnormal methionine metabolism in alcoholic liver injury.
Lu S, Tsukamoto H, Mato J.
USC Liver Disease Research Center, USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases, Keck School of Medicine USC, 90033, Los Angeles, CA, USA

Methionine matabolism occurs mostly in the liver through the formation of S-adenosylmethionine (SAM) in a reaction catalyzed by methionine adenosyltransferase (MAT). S-adenosylmethionine is the principal biologic methyl donor, a precursor for polyamines, and in liver, it is also a precursor for reduced glutathione (GSH). Liver-specific and non-liver-specific MAT are products of two different genes, MAT1A and MAT2A, respectively. Mature liver expresses MAT1A, whereas MAT2A is expressed in extrahepatic tissues and induced during liver growth and de-differentiation. The type of MAT expressed by the cell affects the steady-state SAM level, DNA methylation, and growth rate. This has been demonstrated further by using the MAT1A knockout mouse model in which hepatic SAM and GSH levels decrease, the liver becomes larger and more susceptible to injury, and steatohepatitis develops spontaneously. Altered methionine metabolism in alcoholic liver disease results in decreased transmethylation and transsulfuration, changes that may play important pathogenic roles. Major changes include a relative switch in MAT expression; decreased hepatic SAM, GSH, and DNA methylation levels; decreased homocysteine metabolism; and hyperhomocysteinemia. Consequences of hepatic DNA hypomethylation include increased expression of c-myc and DNA strand break accumulation. One possible consequence of hyperhomocysteinemia is increased fibrogenesis. Abnormal methionine metabolism may also occur in Kupffer cells, which express both forms of MAT. If SAM levels also decrease in these cells, this may contribute to the induction of tumor necrosis factor (TNF) expression and release. In summary, altered hepatic methionine metabolism can have serious consequences that affect not only hepatocytes, but also hepatic stellate and Kupffer cells. These changes can lead to impaired antioxidant defense, altered gene expression, promotion of fibrogenesis, and even hepatocarcinogenesis.

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Alcohol 2002 Jul;27(3):151
Role of S-adenosyl-L-methionine in the treatment of alcoholic liver disease. introduction and
summary of the symposium.
Purohit V, Russo D.
Biomedical Research Branch/Division of Basic Research, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 6000 Executive Boulevard, Suite 402, 20892-7003, Bethesda, MD, USA

The National Institute on Alcohol Abuse and Alcoholism and the Office of Dietary Supplements, National Institutes of Health, sponsored a symposium on "Role of S-Adenosyl-L-Methionine (SAMe) in the Treatment of Alcoholic Liver Disease" in Bethesda, Maryland, September 2001. Alcoholic liver disease (ALD) is a major cause of illness and death in the United States. Oxidant stress plays a key role in pathogenesis of liver disease. S-Adenosyl-L-methionine, a dietary supplement, is the methyl donor for biochemical methylation reactions and a precursor of glutathione, the main hepatocellular antioxidant. S-Adenosyl-L-methionine has been shown to attenuate liver injury caused by alcohol and other hepatotoxins in some animal models. Understanding the mechanisms by which SAMe attenuates liver injury caused by alcohol may provide useful information for full-scale human clinical trials. For this symposium, seven speakers were invited to address the following issues: (1) impaired methionine metabolism in alcoholic liver injury; (2) regulation of liver function by SAMe; (3) folate deficiency, methionine metabolism, and alcoholic liver injury; (4) attenuating effect of SAMe on ALD in experimental animals; (5) SAMe and mitochondrial glutathione depletion in ALD; (6) SAMe and cytokine production in liver injury; and (7) role of SAMe in the prevention of hepatocarcinogenesis. The presentations of this symposium support the suggestion that SAMe may have potential to treat ALD by (1) acting as a precursor of antioxidant glutathione, (2) repairing mitochondrial glutathione transport system, (3) attenuating toxic effects of proinflammatory cytokines, and (4) increasing DNA methylation. Further studies are required to evaluate the safety and effectiveness of SAMe treatment.

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Liver 2002 Jun;22(3):245-51
Single nucleotide polymorphisms and microsatellite alleles of tumor necrosis factor alpha and interleukin-10 genes and the risk of advanced chronic alcoholic liver disease.
Ladero JM, Fernandez-Arquero M, I Tudela J, Agundez JA, Diaz-Rubio M, Benitez J, De La Concha EG.
Departments of Gastroenterology and Immunology, Hospital Clinico San Carlos, Medical School, Complutense University, Madrid, and Department of Pharmacology, Medical School, University of Extremadura, Badajoz, Spain.

BACKGROUND: Only a minority of ethanol abusers develop advanced chronic alcoholic liver disease (CALD). In CALD there is a disbalance between TNFalpha and IL-10, which may be modulated by several polymorphisms at both genetic loci. Our aim has been to elucidate the possible relation between these polymorphisms and the risk of CALD. PATIENTS AND METHODS: 147 patients with advanced CALD and 355 healthy controls (all white Spaniards) were included. TNFalpha biallelic single nucleotide polymorphisms (SNP) at positions -238, -308, and -376 and IL-10 biallelic SNP at positions -597, - 824, and - 1087 were investigated by polymerase chain reaction (PCR) amplification and dot blot hybridization. Moreover, polymorphic microsatellites TNFa, TNFb, IL-10.R and IL-10.G were investigated in a multiplex PCR and alleles were estimated in an automatic sequencer. RESULTS: No differences were found in the distribution of any of the studied polymorphisms, except by an excess of the haplotype formed by the allele 11 of the microsatellite IL-10.G and the GCC arrangement of the SNPs at the promoter of IL-10 gene in patients (15.7 vs. 8.24%, odds ratio: 2.08, 95% C.I. = 1.31-3.31). CONCLUSIONS: The studied polymorphisms at TNFalpha and IL-10 genetic loci are not clearly related to the risk of CALD. The excess of G11-GCC haplotype found in CALD patients needs independent confirmation.

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Alcohol 2002 May;27(1):53-61
Monocyte activation in alcoholic liver disease.
McClain CJ, Hill DB, Song Z, Deaciuc I, Barve S.
Department of Medicine, University of Louisville Medical Center, 40292, Louisville, KY, USA

Activated monocytes and macrophages have been postulated to play an important role in the pathogenesis of alcoholic liver disease (ALD). Monocyte activation can be documented by measurement of neopterin, adhesion cell molecules, and certain proinflammatory cytokines and chemokines. We first became interested in the role of monocytes and monocyte-derived cytokines in ALD in relation to altered zinc metabolism that occurs regularly in ALD. Patients with ALD have hypozincemia, which responds poorly to oral zinc supplementation. We have shown that in ALD monocytes make a low-molecular-weight substance that, when injected into rabbits, causes prominent hypozincemia. Subsequently, multiple cytokines [especially tumor necrosis factor (TNF) and interleukin (IL)-8] have been shown to be overproduced by monocytes in ALD. We initially showed that monocytes in ALD spontaneously produce TNF and overproduce TNF in response to a lipopolysaccharide (LPS) stimulus, and this could be attenuated by antioxidants in vitro and in vivo. Alterations in the endotoxin-binding protein LPS-binding protein, in CD14, and in the endotoxin receptor Toll-like receptor 4 all may play roles in enhanced proinflammatory cytokine signaling in ALD. Moreover, several groups have documented increased TNF receptor density in monocytes in ALD. Inadequate negative regulation of TNF occurs at multiple levels in ALD. This includes decreased monocyte production of the important antiinflammatory cytokine IL-10 and blunted response to the antiinflammatory properties of adenosine. Finally, generation of reactive oxygen species (which occurs during alcohol metabolism) and products of lipid peroxidation induce production of cytokines, such as TNF and IL-8. In conclusion, there are multiple overlapping potential mechanisms for enhanced proinflammatory cytokine production by monocytes in ALD. We postulate that activation of monocytes and macrophages with subsequent proinflammatory cytokine production plays an important role in certain metabolic complications of ALD and is a component of the liver injury of ALD.

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Postgrad Med J 2002 Mar;78(917):135-41
Liver transplantation for chronic liver disease: advances and controversies in an era of organ shortages.
Prince MI, Hudson M.
Freeman Hospital Liver Unit, Freeman Hospital, Newcastle upon Tyne, UK. Martin.prince@doctors.net.uk

Since liver transplantation was first performed in 1968 by Starzl et al, advances in case selection, liver surgery, anaesthetics, and immunotherapy have significantly increased the indications for and success of this operation. Liver transplantation is now a standard therapy for many end stage liver disorders as well as acute liver failure. However, while demand for cadaveric organ grafts has increased, in recent years the supply of organs has fallen. This review addresses current controversies resulting from this mismatch. In particular, methods for increasing graft availability and difficulties arising from transplantation in the context of alcohol related cirrhosis, primary liver tumours, and hepatitis C are reviewed. Together these three indications accounted for 42% of liver transplants performed for chronic liver disease in the UK in 2000. Ethical frameworks for making decisions on patients' suitability for liver transplantation have been developed in both the USA and the UK and these are also reviewed.

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Free Radic Biol Med 2002 Jan 15;32(2):110-4
Free radical mechanisms in immune reactions associated with alcoholic liver disease.
Albano E.
Department of Medical Sciences, University Amedeo Avogadro of East Piedmont, Novara, Italy. albano@med.unipmn.it

Immune reactions toward the liver have been implicated in the pathogenesis of alcoholic liver disease (ALD), however the antigens involved are still poorly characterized. The contribution of free radical mechanisms to the immune reactions associated with ALD first emerged from the observation that the binding of hydroxyethyl free radicals (HER) to hepatic proteins, including cytochrome P4502E1 (CYP2E1), stimulates the production of specific antibodies in both alcohol-fed rats and alcoholic patients. We have subsequently observed that ALD patients have increased titers of antibodies directed against protein adducts with different lipid peroxidation products and antigens derived from the combination of malonildialdehyde and acetaldehyde. Free radical mechanisms can also contribute in promoting the autoimmune reactions often associated with ALD. Indeed, we have observed that antiphospholipid antibodies present in more than 50% of ALD patients recognize oxidized cardiolipin complexed with beta2-glycoprotein 1. Furthermore, a strict association between anti-HER IgG and the development of autoantibodies against CYP2E1 indicates that CYP2E1 modification by HER might promote anti-CYP2E1 autoreactivity in subjects with alcoholic cirrhosis. Altogether, these observations suggest the importance of ethanol-induced oxidative stress in stimulating immune reactions towards both liver allo-and self-antigens.

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Hepatology 2002 Feb;35(2):425-32
Expression of interferon alfa signaling components in human alcoholic liver disease.
Nguyen VA, Gao B.
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.

Interferon alfa (IFN-alpha) is currently the only well-established therapy for viral hepatitis. However, its effectiveness is much reduced (<10%) in alcoholic patients. The mechanism underlying this resistance is not fully understood. In this study, we examined the expression of IFN-alpha signaling components and its inhibitory factors in 9 alcoholic liver disease (ALD) and 8 healthy control liver tissues. In comparison with normal control livers, expression of IFN-beta, IFN-alpha receptor 1/2, Jak1, and Tyk2 remained unchanged in ALD livers, whereas expression of IFN-alpha, signal transducer and activator of transcription factor 1 (STAT1), and p48 were up-regulated and expression of STAT2 was down-regulated. Expression of antiviral MxA a karyophilic 75 kd protein induced by IFN in mouse cells carrying the influenza virus resistance allele Mx(+) and 2'-5' oligoadenylate synthetase (OAS) proteins was not regulated, whereas expression of double-stranded RNA-activated protein kinase (PKR) was decreased by 55% in ALD livers. Three families of inhibitory factors for the JAK-STAT signaling pathway were examined in ALD livers. Members of the suppressor of cytokine signaling (SOCS) family, including SOCS 1, 2, 3, and CIS, and the protein tyrosine phosphatases, including Shp-1, Shp-2, and CD45, were not up-regulated in ALD livers, whereas the phosphorylation of and protein levels of p42/44 mitogen-activated protein kinase (p42/44MAP kinase) were increased about 3.9- and 3.2-fold in ALD livers in comparison with normal control livers, respectively. In conclusion, these findings suggest that chronic alcohol consumption down-regulates STAT2 and PKR, but up-regulates p42/44 mitogen-activated protein kinase (p42/44MAP kinase), which may cause down-regulation of IFN-alpha signaling in the liver of ALD patients.

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Free Radic Biol Med 2002 Jan 1;32(1):11-6
Contribution of mitochondria to oxidative stress associated with alcoholic liver disease.
Bailey SM, Cunningham CC.
Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham, 1530 3rd Ave. South, RPHB 317, Birmingham, AL 35294, USA. sbailey@ms.soph.uab.edu

The importance of oxidative stress in the development of alcoholic liver disease has long been appreciated. The mechanism by which ethanol triggers an increase in reactive oxygen species in the liver is complex, however, recent findings suggest that the mitochondrion may contribute significantly to the overall increase in oxidant levels in hepatocytes exposed to ethanol acutely or chronically. This review is focused on observations which indicate that the ability of ethanol to increase mitochondrial reactive oxygen species production is linked to its metabolism via oxidative processes and/or ethanol-related alterations to the mitochondrial electron transport chain. Furthermore, the capacity of ethanol-elicited increases in reactive oxygen species to oxidatively modify and inactivate mitochondrial proteins is highlighted as a mechanism by which ethanol might further disrupt the structure and function of mitochondria.

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Drugs 2001;61(14):2035-63
The use of silymarin in the treatment of liver diseases.
Saller R, Meier R, Brignoli R.
Abteilung Naturheilkunde, University Hospital Zurich, Switzerland.

The high prevalence of liver diseases such as chronic hepatitis and cirrhosis underscores the need for efficient and cost-effective treatments. The potential benefit of silymarin (extracted from the seeds of Silybum marianum or milk thistle) in the treatment of liver diseases remains a controversial issue. Therefore, the objective of this review is to assess the clinical efficacy and safety of silymarin by application of systematic approach. 525 references were found in the databases, of which 84 papers were retained for closer examination and 36 were deemed suitable for detailed analysis. Silymarin has metabolic and cell-regulating effects at concentrations found in clinical conditions, namely carrier-mediated regulation of cell membrane permeability, inhibition of the 5-lipoxygenase pathway, scavenging of reactive oxygen species (ROS) of the R-OH type and action on DNA-expression, for example, via suppression of nuclear factor (NF)-kappaB. Pooled data from case record studies involving 452 patients with Amanita phalloides poisoning show a highly significant difference in mortality in favour of silibinin [the main isomer contained in silymarin] (mortality 9.8% vs 18.3% with standard treatment; p < 0.01). The available trials in patients with toxic (e.g. solvents) or iatrogenic (e.g. antispychotic or tacrine) liver diseases, which are mostly outdated and underpowered, do not enable any valid conclusions to be drawn on the value of silymarin. The exception is an improved clinical tolerance of tacrine. In spite of some positive results in patients with acute viral hepatitis, no formally valid conclusion can be drawn regarding the value of silymarin in the treatment of these infections. Although there were no clinical end-points in the four trials considered in patients with alcoholic liver disease, histological findings were reported as improved in two out of two trials, improvement of prothrombin time was significant (two trials pooled) and liver transaminase levels were consistently lower in the silymarin-treated groups. Therefore, silymarin may be of use as an adjuvant in the therapy of alcoholic liver disease. Analysis was performed on five trials with a total of 602 patients with liver cirrhosis. The evidence shows that, compared with placebo, silymarin produces a nonsignificant reduction of total mortality by -4.2% [odds ratio (OR) 0.75 (0.5 - 1.1)]; but that, on the other hand, the use of silymarin leads to a significant reduction in liver-related mortality of-7% [OR: 0.54 (0.3 - 0.9); p < 0.01]. An individual trial reported a reduction in the number of patients with encephalopathy of -8.7% (p = 0.06). In one study of patients with cirrhosis-related diabetes mellitus, the insulin requirement was reduced by -25% (p < 0.01). We conclude that available evidence suggests that silymarin may play a role in the therapy of (alcoholic) liver cirrhosis. Silymarin is has a good safety record and only rare case reports of gastrointestinal disturbances and allergic skin rashes have been published. This review does not aim to replace future prospective trials aiming to provide the 'final' evidence of the efficacy of silymarin.

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Arch Intern Med 2001 Oct 8;161(18):2247-52
Effect of maximal daily doses of acetaminophen on the liver of alcoholic patients: a randomized, double-blind, placebo-controlled trial.
Kuffner EK, Dart RC, Bogdan GM, Hill RE, Casper E, Darton L.
Rocky Mountain Poison and Drug Center, 1010 Yosemite Cir, Denver, CO 80230, USA. EKuffner@rmpdc.org

BACKGROUND: Retrospective reports suggest that therapeutic doses of acetaminophen may be associated with fulminant hepatic failure and death in alcoholic patients. Millions of patients use acetaminophen; the prevalence of alcoholism in the United States is 5% to 10%. OBJECTIVE: To determine if hepatic injury was associated with maximal therapeutic dosing of acetaminophen to chronic alcohol abuse patients immediately following cessation of alcohol intake (the presumed time of maximal vulnerability). METHODS: Patients entering an alcohol detoxification center were enrolled in a randomized, double-blind, placebo-controlled trial. Exclusion criteria were baseline values of aspartate or alanine aminotransferase greater than 120 U/L, international normalized ratio greater than 1.5, serum acetaminophen level greater than 20 mg/L, or a history of ingesting more than 4 g/d of acetaminophen. Acetaminophen, 1000 mg, or placebo was administered orally 4 times daily for 2 consecutive days and liver test results were monitored for 2 more days. Acetaminophen was not administered until the alcohol had been eliminated. RESULTS: There were 102 patients in the acetaminophen-treated group and 99 patients in the placebo-treated (control) group. Demographic data, alcohol history, and baseline blood test results were similar in both groups. The mean (SD) aspartate aminotransferase level on day 4 was 38.0 +/- 26.7 U/L in the acetaminophen-treated group and 37.5 +/- 27.6 U/L in the placebo-treated group. There were 4 patients in the acetaminophen-treated group and 5 in the placebo-treated group who developed an increase in their serum aspartate aminotransferase level to greater than 120 U/L; it did not exceed 200 U/L in any patient. The mean (SD) international normalized ratio on day 4 was 0.96 +/- 0.09 in the acetaminophen-treated group and 0.98 +/- 0.11 in the placebo-treated group. CONCLUSION: Repeated administration of the maximum recommended daily doses of acetaminophen to long-term alcoholic patients was not associated with evidence of liver injury.

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Baillieres Clin Gastroenterol 1993 Sep;7(3):581-608
Aetiology and pathogenesis of alcoholic liver disease.
Lieber CS.
Mount Sinai School of Medicine (CUNY).

Until the 1960s, liver disease of the alcoholic patient was attributed exclusively to dietary deficiencies. Since then, however, our understanding of the impact of alcoholism on nutritional status has undergone a progressive evolution. Alcohol, because of its high energy content, was at first perceived to act exclusively as 'empty calories' displacing other nutrients in the diet, and causing primary malnutrition through decreased intake of essential nutrients. With improvement in the overall nutrition of the population, the role of primary malnutrition waned and secondary malnutrition was emphasized as a result of a better understanding of maldigestion and malabsorption caused by chronic alcohol consumption and various diseases associated with chronic alcoholism. At the same time, the concept of the direct toxicity of alcohol came to the forefront as an explanation for the widespread cellular injury. Some of the hepatotoxicity was found to result from the metabolic disturbances associated with the oxidation of ethanol via the liver alcohol dehydrogenase (ADH) pathway and the redox changes produced by the generated NADH, which in turn affects the metabolism of lipids, carbohydrates, proteins and purines. Exaggeration of the redox change by the relative hypoxia which prevails physiologically in the perivenular zone contributes to the exacerbation of the ethanol-induced lesions in zone 3. In addition to ADH, ethanol can be oxidized by liver microsomes: studies over the last twenty years have culminated in the molecular elucidation of the ethanol-inducible cytochrome P450IIE1 (CYP2E1) which contributes not only to ethanol metabolism and tolerance, but also to the selective hepatic perivenular toxicity of various xenobiotics. Their activation by CYP2E1 now provides an understanding for the increased susceptibility of the heavy drinker to the toxicity of industrial solvents, anaesthetic agents, commonly prescribed drugs, 'over the counter' analgesics, chemical carcinogens and even nutritional factors such as vitamin A. Ethanol causes not only vitamin A depletion but it also enhances its hepatotoxicity. Furthermore, induction of the microsomal pathway contributes to increased acetaldehyde generation, with formation of protein adducts, resulting in antibody production, enzyme inactivation and decreased DNA repair; it is also associated with a striking impairment of the capacity of the liver to utilize oxygen. Moreover, acetaldehyde promotes glutathione depletion, free-radical mediated toxicity and lipid peroxidation. In addition, acetaldehyde affects hepatic collagen synthesis: both in vivo and in vitro (in cultured myofibroblasts and lipocytes), ethanol and its metabolite acetaldehyde were found to increase collagen accumulation and mRNA levels for collagen. This new understanding of the pathogenesis of alcoholic liver disease may eventually improve therapy with drugs and nutrients.

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