BARCELONA . SPAIN ALCOHOLIC LIVER DISEASE 18 - 19/2012
EASL POSTGRADUATE COURSE ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 COURSE DIRECTORS: R. Bataller, USA A. Hadengue, Switzerland F. Zoulim, France EASL EDUCATIONAL COUNCILLORS: J.F. Dufour, Switzerland F. Zoulim, France 2 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE TABLE OF CONTENTS BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 3 WELCOME MESSAGE 3 WELCOME MESSAGE 4 EASL GOVERNING BOARD Dear Colleagues, 5 PROGRAMME 8 POSTGRADUATE COURSE FACULTY It is with great pleasure that we welcome you to the Postgraduate Course of the International Liver Congress™ 2012, the 47th annual meeting of the European Association for Study of the Liver. CONTRIBUTORS: 11 H. CORTEZ-PINTO, PORTUGAL 17 N. SHERON, UK 25 S. ZAKHARI, USA 32 F. STICKEL, SWITZERLAND 38 S. LOTERSZTAJN, FRANCE 43 F. MARRA, ITALY 54 T. ROSKAMS, BELGIUM 59 S. MUELLER, GERMANY 76 A. GUAL, SPAIN 81 G. ADDOLORATO, ITALY 87 J. FERNÁNDEZ-SOLÀ, SPAIN 93 E.H. FORREST, UK 98 F. NEVENS, BELGIUM 103 A. HADENGUE, SWITZERLAND 112 J-C. DUCLOS-VALLÉE, FRANCE 116 J. NEUBERGER, UK 121 H. SEITZ, GERMANY 131 T. DECAENS, FRANCE 136 G.P. PAGEAUX, FRANCE 140 P. BURRA, ITALY 147 B. GAO, USA 152 L. SPAHR, SWITZERLAND 158 P. ANDERSON, UK 165 D.W. LACHENMEIER, GERMANY The topic for this year’s Postgraduate Course is Alcoholic Liver Disease, the importance of which is indisputable given that it remains the most common cause of cirrhosis and liver mortality in Europe. We have attempted to cover all aspects of alcoholic liver disease from public health to transplantation in order to provide a comprehensive educational opportunity. The programme includes sessions on the recognition and management of alcohol dependence which some of you may consider to be outside your field of expertise. However, with the increasing burden of alcoholic liver disease in many countries it increasingly defaults to the hepatologists to provide or commission appropriate services for this problem. The EASL Governing Board are indebted to the course organisers; Ramon Bataller, Antoine Hadengue and Fabien Zoulim for putting the programme together using case-based discussions to improve the educational value of the course. In addition, we would like to thank Philippe Mathurin, Ramon and Antoine, together with the other panellists for putting together EASL’s Clinical Practice Guidelines on Alcoholic Liver Disease which they will present as part of the course. We hope you have the opportunity to enjoy the Postgraduate Course as well as the rest of the International Liver Congress™. Prof. Mark Thursz, MD FRCP Prof. Markus Peck-Radosavljevic EASL SECRETARY GENERAL EASL VICE-SECRETARY 4 POSTGRADUATE COURSE SYLLABUS EASL GOVERNING BOARD SECRETARY GENERAL Mark Thursz, London, UK VICE-SECRETARY Markus Peck-Radosavljevic, Vienna, Austria TREASURER Mauro Bernardi, Bologna, Italy SCIENTIFIC COMMITTEE Matías A. Avila. Pamplona, Spain Frank Lammert, Homburg, Germany George V. Papatheodoridis, Athens, Greece Daniele Prati, Lecco, Italy Tania Roskams, Leuven, Belgium EDUCATIONAL COUNCILLORS Jean-Francois Dufour, Bern, Switzerland Fabien Zoulim, Lyon, France EU POLICY COUNCILLOR Dominique-Charles Valla, Paris, France ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 5 PROGRAMME WEDNESDAY, APRIL 18, 2012 11:30-17:30 Postgraduate Course ALCOHOLIC LIVER DISEASE Course Directors: R. Bataller, USA A. Hadengue, Switzerland F. Zoulim, France 11:30 Introduction A. Hadengue, Switzerland HALL A EPIDEMIOLOGICAL AND PUBLIC HEALTH ISSUES 11:35 Q&A INTERACTIVE SESSION: QUESTIONS 11:40 INCREASING BURDEN OF ALCOHOLIC LIVER DISEASE IN EUROPE H. Cortez-Pinto, Portugal 11:55 CURRENT ACTIONS TO CONFRONT ALCOHOLIC LIVER DISEASE IN EUROPE N. Sheron, UK 12:10 PATTERNS OF ALCOHOL INTAKE AND ALD: EFFECTS OF BINGE DRINKING ON THE LIVER S. Zakhari, USA 12:25 Q&A INTERACTIVE SESSION: ANSWERS NATURAL HISTORY AND MECHANISMS 12:35 Q&A INTERACTIVE SESSION: QUESTIONS 12:40 NATURAL HISTORY OF ALD: ROLE OF ENVIRONMENTAL AND GENETIC FACTORS F. Stickel, Switzerland 12:55 NOVEL MECHANISMS OF ALCOHOLIC STEATOHEPATITIS S. Lotersztajn, France 13:10 MECHANISMS OF ALCOHOL-INDUCED LIVER FIBROSIS F. Marra, Italy 13:25 Q&A INTERACTIVE SESSION: ANSWERS 13:35 – 14:00 LUNCH 6 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 WEDNESDAY, APRIL 18, 2012 continued THURSDAY, APRIL 19, 2012 THE PATIENT WITH CHRONIC ALD 08:30-12:00 7 HALL A Postgraduate Course ALCOHOLIC LIVER DISEASE Course Directors: R. Bataller, USA A. Hadengue, Switzerland F. Zoulim, France 14:00 Q&A INTERACTIVE SESSION: CLINICAL CASE (QUESTIONS) Fellow: F. Artru, France 14:05 HISTOLOGICAL ASSESSMENT OF ALD T. Roskams, Belgium 14:20 NONINVASIVE TOOLS IN THE DIAGNOSIS OF ALD S. Mueller, Germany 08:30 Q&A INTERACTIVE SESSION: CASE PRESENTATION (QUESTIONS) Fellow: N. Goossens, Switzerland 14:35 ABUSE OR DEPENDENCE? ASSESSING THE ALCOHOLIC PATIENT IN THE CLINIC A. Gual, Spain 08:35 ALCOHOL CONSUMPTION AS A CO-FACTOR FOR OTHER LIVER DISEASES H. Seitz, Germany 14:50 MANAGEMENT OF ALCOHOL DEPENDENCE IN PATIENTS WITH ALD G. Addolorato, Italy 08:50 HEPATOCELLULAR CARCINOMA: IS IT DIFFERENT IN PATIENTS WITH ALD? T. Decaens, France 15:05 EXTRAHEPATIC INVOLVEMENT IN PATIENTS WITH ALD J. Fernández-Solà, Spain 09:05 15:20 Q&A INTERACTIVE SESSION: CLINICAL CASE (ANSWERS) A. Louvet, France EVALUATION AND SELECTION OF CANDIDATES FOR LIVER TRANSPLANTATION G.P. Pageaux, France 09:20 PATIENTS WITH ALD AND LIVER TRANSPLANTATION: SPECIFIC ISSUES P. Burra, Italy 09:35 Q&A INTERACTIVE SESSION: CASE PRESENTATION (ANSWERS) A. De Gottardi, Switzerland 10:00-10:30 COFFEE BREAK 15:35-16:00 COFFEE BREAK THE ACUTELY ILL PATIENT 16:00 Q&A INTERACTIVE SESSION: CASE PRESENTATION (QUESTIONS) Fellow: J.T. Altamirano, Spain 16:05 MANAGEMENT OF ALCOHOL WITHDRAWAL E.H. Forrest, UK 16:20 16:35 FUTURE PROSPECTS IN ALD 10:30 NOVEL TARGETS FOR THERAPY IDENTIFIED IN TRANSLATIONAL STUDIES B. Gao, USA ALCOHOLIC HEPATITIS OR DECOMPENSATED CIRRHOSIS: DIAGNOSTIC AND PROGNOSTIC ISSUES F. Nevens, Belgium 10:45 STEM CELLS IN ALD: THE ROAD FROM ANIMAL MODELS TO HUMAN STUDIES L. Spahr, Switzerland MANAGEMENT OF ALCOHOLIC HEPATITIS A. Hadengue, Switzerland 11:00 CURRENT POLICIES TO DECREASE THE HARM DONE BY ALCOHOL IN EUROPE 11:15 ILLEGALLY PRODUCED SPIRITS IN EASTERN EUROPE: TO WHAT EXTENT AND AT WHAT RISK D.W. Lachenmeier, Germany 11:30 PRESENTATION OF THE EASL CLINICAL PRACTICAL GUIDELINES ON ALCOHOLIC LIVER DISEASE P. Mathurin, France 11:55 CONCLUDING REMARKS R. Bataller, USA CONTROVERSY: CAN WE OFFER LIVER TRANSPLANTATION TO PATIENTS WITH ALCOHOLIC HEPATITIS? 16:50 LONG-TERM MANAGEMENT OF ALD YES J-C. Duclos-Vallée, France 17:05 NO J. Neuberger, UK 17:20 Q&A INTERACTIVE SESSION: CASE PRESENTATION (ANSWERS) J. Caballería, Spain 8 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 9 Bin GAO Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, USA POSTGRADUATE COURSE FACULTY Nicolas GOOSSENS Division of Gastroenterology and Hepatology, Cantonal Hospital, Geneva, Switzerland Antoni GUAL Alcohol Unit, Hospital Clínic, Barcelona, Spain COURSE DIRECTORS: EASL EDUCATIONAL COUNCILLORS: Antoine HADENGUE Division of Gastroenterology and Hepatology, Cantonal Hospital, Geneva, Switzerland R. Bataller, USA A. Hadengue, Switzerland F. Zoulim, France J. Dufour, Switzerland F. Zoulim, France Dirk LACHENMEIER Alcohol Laboratory, Chemical and Veterinary Investigation Agency Karlsruhe, Karlsruhe, Germany Alexandre LOUVET Department of Digestive Diseases, Hôpital Huriez, Lille, France Giovanni ADDOLORATO Department of Internal Medicine, Catholic University of Rome, Rome, Italy Sophie LOTERSZTAJN Inserm U955, Hospital Henri Mondor, Créteil, France Jose T. ALTAMIRANO Liver Unit, Liver Fibrosis Laboratory, Hospital Clinic, Barcelona, Spain Fabio MARRA Department of Internal Medicine, University of Florence, Florence, Italy Peter ANDERSON Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK Philippe MATHURIN Department of Digestive Diseases, Hôpital Huriez, Lille, France Florent ARTRU Department of Digestive Diseases, Hôpital Huriez, Lille, France Sebastian MUELLER Department of Medicine, Salem Medical Centre and Centre for Alcohol Research, University of Heidelberg, Heidelberg, Germany Ramon BATALLER Division of Gastroenterology & Hepatology, University of North Carolina at Chapel Hill, UNC, USA Patrizia BURRA Multivisceral Transplant Unit, Department of Surgical, Oncological and Gastroenterological Sciences, Padova University Hospital, Padova, Italy Frederik NEVENS Department Liver and Biliopancreatic diseases, University Hospital Gasthuisberg, K.U. Leuven, Belgium James NEUBERGER Liver Unit, Queen Elizabeth Hospital, Birmingham, UK Juan CABALLERÍA Liver Unit, Hospital Clinic, Barcelona, Spain Georges-Philippe PAGEAUX Department of Hepato-Gastroenterology, CHU Saint Eloi, Montpellier, France Helena CORTEZ-PINTO Department of Gastroenterology, Hospital of Santa Maria, Unit of Nutrition and Metabolism, FML, Instituto de Medicina Molecular (IMM), Lisbon, Portugal Tania ROSKAMS Department of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium Andrea DE GOTTARDI University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland Helmut SEITZ Centre of Alcohol Research, University of Heidelberg and Department of Medicine, Salem Medical Centre, Heidelberg, Germany Thomas DECAENS Department of Hepatology, Henri Mondor Hospital, University of Paris, Créteil, France Nick SHERON Department of Clinical Hepatology, University of Southampton, Southampton, UK Jean-Charles DUCLOS-VALLÉE Centre Hépato-Biliaire, Hôpital Paul-Brousse, Villejuif, France Laurent SPAHR Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland Jean Francois DUFOUR University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland Felix STICKEL Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Switzerland Joaquim FERNÁNDEZ-SOLÀ Alcohol Unit, Department of Medicine, Hospital Clínic, University of Barcelona, Spain Sam ZAKHARI Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, USA Ewan FORREST Department of Gastroenterology, Glasgow Royal Infirmary, Castle Street, Glasgow, UK Fabien ZOULIM Liver Department, Hôtel Dieu Hospital & Hepatitis Research Laboratory, Lyon, France BARCELONA . SPAIN APRIL 18 - 19/2012 COME AND VISIT THE EASL BOOTH RENEW YOUR MEMBERSHIP JOIN THE EASL COMMUNITY TODAY EASL Office [email protected] www.easl.eu [email protected] THE INTERNATIONAL LIVER CONGRESSTM 2012 11 INCREASING BURDEN OF ALCOHOLIC LIVER DISEASE IN EUROPE Helena Cortez-Pinto Lisbon, Portugal E-mail: [email protected] KEY POINTS • Alcohol is the main cause of liver disease in Europe. The prevalence of alcoholic disease is increasing mostly in Eastern countries but also in some Western countries such as United Kingdom, Ireland and Finland. • Alcoholic liver disease is partially preventable through policies that reduce alcohol consumption, since a good correlation between alcohol consumption and cirrhosis mortality has been demonstrated. Policies that reduce the availability of alcohol either though pricing increase or reducing hours of sale, have shown to be the more effective. • Binge drinking is increasing and more data is needed on its impact on liver disease. INTRODUCTION Alcoholic liver disease (ALD) is the main cause of liver-related mortality in Europe. However, viral- and other liver diseases have attracted much more attention in what concerns investigation in the past decades. This is very well illustrated by the Death-To-Trials ratio score (ETOh), that is the ratio of estimated deaths attributed to a disease to the number of trials focused on that disease. Alcoholic liver disease has a very high score when compared for example with hepatitis C virus, 358 vs 4.8, thus demonstrating that there is a lack of studies performed on ALD. Among the causes for the relative low interest for ALD, may be the fact that other liver diseases have more potential to be treated, or that alcoholic liver disease affects individuals that are poorer or less influential in Society. However, recent years have witnessed advances in the pathogenesis and treatment of ALD. Furthermore, a remarkable increase in the frequency of alcohol consumption, and consequently of ALD has been demonstrated mostly in Europe, and particularly in Eastern European countries. On the other hand, it is likely that in short-term, viral-related diseases are going to become much less important. Consequently, it is foreseeable that metabolic and alcoholic liver disease will become the main focus of research in liver disease. EFFECT OF ALCOHOL CONSUMPTION ON MORBIDITY AND MORTALITY Alcohol consumption accounts for 3.8% of global mortality and 4.6% of DALYs, that are the sum of life years lost due to premature death or years lived in disability, according to the World Health Organization (WHO). If Europe alone is considered, these numbers are higher, with 6.5% of all deaths and 11.6% of DALY’s (Figure 1 and 2). It is of note that males are predominantly affected, with 17.3% of male and 4.4% of female DALY’s in Europe, after accounting for health benefits. Also young people share a disproportionate amount of the burden of disease, with alcohol being responsible for over 10% and 25% of female and male youth mortality, respectively. Altogether, alcohol consumption ranks third as a cause of premature death and disability in the European Union (EU), just after tobacco smoking and high blood pressure (1). Indeed, liver disease represents 9.5% of alcohol-related DALY’s worldwide, although these rates may vary according to different countries and areas of the world (2). For instance in Portugal, liver-related DALY’s accounted for 31.5% of all alcohol-related DALY´s. 12 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE PREVALENCE AND TRENDS IN ALCOHOL CONSUMPTION AND ALCOHOLIC LIVER DISEASE The trends in alcohol consumption and alcohol-related harm vary significantly among different countries and areas of Europe as well as according to policies and interventions in each country. In fact, in the period 1990‒2006, there have been substantial fluctuations with decrease, increase and then stabilization. There is evidence of a very marked disparity in alcohol consumption trends among different countries, with a predominance of Eastern European countries experiencing an increase. Also, the financial crisis in the European Union is probably going to result in an increase in alcohol-related harm. In fact, already a more than three per cent increase in unemployment is associated with as much as a 28 per cent increase in deaths from alcohol use disorders (3). It is difficult to estimate the true prevalence of alcoholic liver disease in the population. A population based study in France, using transient elastography as a screening tool, found that alcohol was the probable cause of one third of the cases of excess fibrosis (4). However, we really need further studies combining serum markers, ultrasound and elastography to better define the real prevalence of compensated and decompensated alcoholic liver disease. Further studies also need more detailed alcohol drinking pattern, since that may have implications on the risk of liver disease. In fact, it is still unclear if the risk is different when alcohol consumption concentrates on one or two days of the week, or if it distributes homogeneously during the week. Also, the effect of binge drinking (by definition more than 5 drinks for men, and more than 4 drinks for women in two hours) on the risk of progression to more advanced forms of ALD is yet ill-defined. Since binge drinking is steeply increasing, mostly in young people, and in some countries, the information would be of great importance. Liver cirrhosis mortality remains the best tool to evaluate the burden and trends of alcoholic liver disease, although it is still subject to important bias, including differences in death certificates accuracy according to different countries, and the reluctance to include alcohol in the death certificate due to legal implications. During the last 30 years, mortality due to liver cirrhosis followed a pattern similar to alcohol consumption, with a large disparity between countries. In fact, it was well shown that per capita alcohol consumption is strongly correlated with liver cirrhosis mortality rates across countries. There have been sharp declines in liver cirrhosis mortality in about half the countries in Europe, mostly Western European countries, such as Austria, France, Germany, Italy, Portugal and Spain, but also in Eastern countries such as Hungary and Romania. On the opposite, impressive increases in liver mortality cirrhosis are seen in Eastern countries, such as Russia, Lithuania, Estonia and Polonia, but also in some Western countries such as United Kingdom and Ireland and Finland (Figure 3). It is of interest that these differences are more evident in the group older than 45 years. Also, incidence of ALD is 2 to 3 times higher in males than females, although frequency between males and females tend to correlate in every country and for each level of consumption (5). Data from the European Liver Transplantation Registry showed that alcohol represents one third of the causes of cirrhosis leading to liver transplantation and is the second cause for liver transplantation (Figure 4). These numbers underscore the importance of alcohol as a cause of liver disease, although still underestimating it, since alcoholics are probably less transplanted than other patients. Also, and according to the same study, there has been a recent increase in the number of patients transplanted due to alcoholic liver disease (6). Another important issue is the recent change in the pattern of alcohol consumption, and how is it going to affect the risk of liver disease. In fact, recent years have shown an increase in the binge drinking pattern, particularly in young people, and there is evidence that binge-drinking can cause liver cirrhosis, with the risk increasing with the number of binge episodes (7). This evidence comes from experimental as well as epidemiological studies. Besides from the effect on the liver, binge has also been associated with an increased risk of atrial fibrillation and ventricular arrhythmias, myocardial infarction, as well as haemorrhagic and ischaemic strokes. Besides from the effect on the liver, it is increasingly recognized that alcohol has a very important role in several other diseases, such as cardiovascular diseases, showing a very strong risk association with BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 13 hypertension, hemorrhagic stroke and cancer. Indeed, alcohol metabolism produces acetaldehyde, strongly involved in alcohol-associated carcinogenesis; in addition, ethanol itself stimulates carcinogenesis by inhibiting DNA methylation and by interacting with retinoid metabolism. The importance of alcohol as a risk for cancer, namely of the oral cavity, pharynx, esophagus, liver, colon, rectum, larynx and female breast have been well recognized. According to the WHO estimates for global burden of disease, more than 389,000 cases of cancer were attributable to alcohol drinking worldwide, thus representing 3.6% of all cancers, (5.2% in men, and 1.7% in women). Similar results were found by the International Agency for Research on Cancer, that alcohol is a risk factor for upper aerodigestive tract cancer (oral cavity, pharynx, hypopharynx, larynx, and esophagus), liver cancer, colorectal cancer, and breast cancer. In fact, it was only recently that the increased risk for breast cancer, even for very low consumptions, was highlighted and documented, with breast cancer comprising 60% of alcohol-attributable cancers, in women. It is also of note that alcohol consumption and smoking has a synergistic effect on the risk of some of these cancers. Alcoholassociated changes in behavior, is also a major cause of intentional and unintentional injuries, either to the drinker or to others. It is also an important cause of professional absenteeism and low performance, as well as family violence and disruption. Alcohol is also a potent teratogen and a cause of neurological and psychiatric disturbances. ECONOMIC BURDEN It was estimated that the total tangible costs of alcohol to the EU in 2003 were about €125 billion (€79bn€220bn), equivalent to 1.3% (0.9–2.4%) of gross domestic product (GDP). Actual spending on alcoholrelated problems accounts for €66 billion of this, while potential production not realized due to absenteeism, unemployment and premature mortality accounts for a further €59 billion. This amount largely exceeds the reported contribution of around 9 billion euros to the goods account balance for the EU. Furthermore, it seems to contribute to health inequalities between and within European Member States, due to more frequent risky alcohol use in lower socioeconomic groups and also to greater mortality from directly alcoholrelated conditions (8). HOW TO DEAL WITH THE PROBLEM Since alcohol is indeed a major health risk factor and simultaneously a heavy economic burden, it becomes obvious that measures need to be taken to change/reduce the pattern of consumption. One the major problems regarding control of alcohol consumption is that drinking alcohol can be harmless and is very strongly rooted in our Society. In fact, it is not constantly harmful as for example tobacco smoking, and this duality results in difficulty in delineating measures to reduce consumption and to implement them. One of the first controversies is what the safe-drinking limit is? In what regards the threshold for liver cirrhosis, Rehm et al. found in a recent meta-analysis, an increased risk of mortality from liver cirrhosis among men and women drinking 12-24g/ethanol per day (9), and a large epidemiological study on Italy, found that there was an increased risk of cirrhosis in those drinking 30 g/ethanol per day. More difficult and controversial is to find a threshold in the case of binge-drinking (7). It is possible that for some diseases there is not a safe limit. For example, in breast cancer, a recent meta-analysis that included 98 studies reported a 10% increase in breast cancer risk per 10 g of alcohol con¬sumed per day, with no definition of a safe threshold. Alcohol policies and their effectiveness Several policy targeted areas have been developed, including information and education, health sector response, community programmes, drink driving policies, availability of alcohol, marketing of alcohol beverages, pricing policies, harm reduction, and reducing the effect of illegal produced alcohol. Regarding interventions on information and education, they are not expensive, but systematic reviews of this programmes showed that they do not particularly affect consumption levels or health outcomes (10), although they are important to convey awareness and knowledge of the problem. Other policies, like drinkdriving, seem to be quite effective, mostly if they are efficiently implemented and rigorously enforced (10). Also, brief interventions to those at-risk seem to be useful. One of the most effective measures is reducing availability of alcohol, either through the pricing policies or the hours and places of sale and minimum purchase age laws (8). In fact, laws that set a minimum age for the purchase of alcohol show clear reduction in drink-driving casualties and other alcohol-related harm. 14 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Also, reduction of the hours or days of sale leads to fewer alcohol-related problems. However, there is evidence that strict restriction can lead to illicit market. Pricing policies have very well demonstrated an inverse correlation between alcohol price and consumption. A recent report commissioned by the EU, concluded that there is a positive relationship between alcohol affordability and alcohol consumption, and also between alcohol consumption and 3 types of harms: traffic injuries, traffic deaths, and liver cirrhosis. The report also concludes that cross-border alcohol consumption due to tax differentials can lead to increases in consumption. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 15 Figure 1 Alcohol-attributable deaths as proportion of all deaths by sex in Europe and World. Data from WHO Global Burden 2004. Undoubtedly, increasing alcohol taxes reduces alcohol consumption and related harm and increases government revenue. The effect tends to be stronger in the long term, delaying the start of drinking, and slowing young people’s progression to heavy drinking. It also reduces young people heavy drinking and the volume of alcohol per occasion, and has a much stronger effect on heavier than on light drinkers. Also, alcohol marketing has a major impact in levels and patterns of consumption, especially in young people. In fact, there is an impressive sophisticated advertising in mainstream media. Powerful marketing campaigns link alcohol brands to sports and cultural activities, through sponsorships, internet, podcasting and mobile phones. It has been shown that exposure to alcohol advertising has an effect on initiation of young drinking and on riskier patterns of youth drinking in 13 longitudinal studies including 38,000 young people. Furthermore, young people likely continue to increase their drinking as they move in their twenties. Also, the effects of exposure are cumulative. Individuals with higher consumptions in their mid-teens tend to be those with heavier consumption, alcohol dependence and alcohol-related harm, including poorer mental health and education outcome, and increased risk of crime, in early adulthood. REFERENCES WHO. Global Status Report on Alcohol 2004. Geneva: World Health Organization; 2004. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 2009;373:2223-33. * Stuckler D, Basu S, Suhrcke M, Coutts A, McKee M. The public health effect of economic crises and alternative policy responses in Europe: an empirical analysis. Lancet 2009;374:315-23. Roulot D, Costes JL, Buyck JF, Warzocha U, Gambier N, Czernichow S, Le Clesiau H, Beaugrand M. Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years. Gut 2011;60:977-84. WHO. European Status Report on Alcohol and Health 2010. Copenhagen; 2010. Burra P, Senzolo M, Adam R, Delvart V, Karam V, Germani G, Neuberger J. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am J Transplant 2010;10:138-48. Mathurin P, Deltenre P. Effect of binge drinking on the liver: an alarming public health issue? Gut 2009;58:613-7. Rabinovich L, Brutscher P-B, Vries H, Tiessen J, Clift J, Reding A. The affordability of alcoholic beverages in the European Union. Understanding the link between alcohol affordability, consumption and harms; 2009. Rehm J, Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, Roerecke M. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev 2010;29:437-45* Anderson P, Chisholm D, Fuhr DC. Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol. Lancet 2009;373:2234-46. Figure 2 Alcohol-attributable disability adjusted life years (DALYs) as proportion of all DALYs by sex in Europe and World. Data from WHO Global Burden 2004. 16 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Figure 3 Mortality from liver cirrhosis among men in three groups of European countries (n=27), 2000-2005. Data from WHO report 2010 Eur-A: 27 countries with very low child and adult mortality: Andorra, Austria, Belgium, Croatia, Cyprus, the Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco, the Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland and the United Kingdom. Eur-B: 17 countries with low child and adult mortality: Albania, Armenia, Azerbaijan, Bosnia and Herzegovina, Bulgaria, Georgia,Kyrgyzstan, Montenegro, Poland, Romania, Serbia, Slovakia, Tajikistan, the former Yugoslav Republic of Macedonia, Turkey, Turkmenistan andUzbekistan. Eur-C: 9 countries with low child but high adult mortality: Belarus, Estonia, Hungary, Kazakhstan, Latvia, Lithuania, Republic of Moldova, the Russian Federation and Ukrain BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 17 ALCOHOLIC LIVER DISEASE IN EUROPE Nick Sheron Southampton, UK E-mail: [email protected] KEY POINTS • Mortality from liver disease is directly proportional to population level alcohol consumption within each country in the EU. • There is a strong evidence base for effective policies which can reduce liver deaths by reducing population level alcohol consumption. • These effective and cost effective policies are based on the 4p’s of the marketing mix: price, product, place of sale and promotion. • The drinks industry are reliant on hazardous and harmful drinkers for around 75% of their turnover in the UK, and by inference many other EU member states. • As with tobacco, the EU liver community will need to be pro-active in countering the sophisticated lobbying of the drinks industry if effective alcohol strategies are to be achieved. INTRODUCTION The European region is the heaviest drinking region in the world and the evidence detailing the burden of ill health and the economic costs attributable to excessive consumption of alcohol is extensive. The World Health Organisation recognises alcohol as the third leading risk factor for poor health in Europe(1), resulting in 200,000 deaths each year with a cost to society of around €125 billion, or 1.3% of gross domestic product(2). Figure 4 Liver transplantion in Europe. Indications in cirrhosis. Data from European Liver Transplantation Registry (ELTR) 2010 Different varieties of harm result from different patterns of drinking alcohol; acute intoxication causes people to put themselves and others at risk and is implicated in sexual and other violence, suicide, accidental death and trauma. Regular heavy drinking can lead to alcohol dependency and chronic ill health. Alcohol is metabolised by the liver, and regular heavy intake causes progressive fibrosis, cirrhosis, liver failure and death. Alcohol-related disease is the most common cause of cirrhosis, liver death rates are a reliable indicator of the harm caused by regular heavy drinking and there is a strong relationship between liver death rates (liver SDR) and overall alcohol consumption which becomes stronger as overall consumption increases (Figure 1). Over the last 30 years liver death rates in the EU have gradually declined in response to changing patterns of alcohol intake. In 1970 the EU liver death rate was 13.25 and in 2007 it had declined to 8.01 (for pre 2004 EU member states) - a reduction of 60%. But this overall decline conceals very large differences between Member States. France and Italy, the countries with the largest decline in liver deaths, have seen three to four-fold reductions in liver mortality. Whereas UK and Finland have seen liver deaths rise by more than five fold over the same period of time (figure 2). These are very dramatic changes in liver mortality and in this paper we examine possible reasons for these changes, and the lessons they may hold for liver clinicians. Drinking cultures Across the EU there are many different cultural behaviours related to alcohol consumption and the nature of the resulting harm differs in terms of its impact on the individual, society and the economy. A traditional distinction has been drawn between northern European countries and their southern European counterparts in terms of alcohol consumption and drinking patterns, and it is tempting to place the origin for these differences back in antiquity. In the epic Babylonian poem Gilgamesh (2700BC) - the fall of the hero Enkidu was precipitated by seduction into drunkenness: “Enkidu drank the beer - seven jugs and became 18 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE expansive and sang with joy, he was elated and his face glowed”. But later he curses “May dregs of beer stain your beautiful lap, may a drunk soil your festal robe with vomit…”. The regular drinking of wine with meals was contrasted with barbarian drinking habits by Diodorus Siculus and Tacitus in the 1st centuries BC and AD, and by Saints Boniface and Bede in the 9th century AD. Epic feats of drunkenness are as much a feature of Celtic and Viking poetry as the battles which they celebrated and epic feats of drunkenness and fighting remain a feature of Anglo-Saxon and Celtic society to this day. Whatever the underlying reasons, these cultural difference are real. In the Eurobarometer alcohol survey of 2002, Ireland, UK and Finland had the highest number of occasions on which people thought they ‘had drunk too much’ and had the lowest percentage of alcohol consumption with meals, with Italy having the highest. Northern European countries have historically controlled demand with strict controls on the supply of alcohol. These include: restrictions on the availability of alcohol (both for on-trade and off-trade sale), restrictions on the number of premises licensed to sell alcohol, limited hours of trade and high prices and state monopolies on alcohol production and trade. In stark contrast, southern European countries had limited policies in place to restrict the availability of alcohol before the 1980s. The nature of the drinks industry in southern Europe is also different, with a large variety of diverse wine producers, and local or regionally produced wines for local consumption. UK Changes in alcohol consumption in the UK have been driven by both cultural and market factors. Marketing - the art of selling - has four basic principles: the four P’s, place, product, price and promotion have all changed in association with a shift from local pubs to sales from supermarkets and local shops. Since 1970 sales of wine and spirits increased - wine more than six-fold and spirits two-fold. Sales of strong lager increased 15-fold and cider six-fold, whereas sales of normal strength beer and lager fell by around 10%. The doubling of wine consumption was influenced by foreign holidays, globalisation and EU membership requiring harmonisation of duty on wine. But the rise of supermarkets also resulted in marked changes in the way that alcohol was promoted, to the extent that alcohol promotions are now used to drive footfall into stores, and stacks of cheap white wine are now routinely placed all over the store to facilitate impulse buying. This is an irresponsible way to sell a toxic dependence inducing drug. The UK House of Commons (HoC) Health Committee quotes Martin Plant: “supermarkets are exhibiting the morality of a crack dealer”(3). The early 1990’s saw the conjunction of plummeting whisky sales as an older generation moved on and the emergence of a new and initially alcohol averse youth culture, leading to intense and successful industry lobbying on alcohol taxation. Duty on spirits was reduced for the next 15 years. Since 1980 spirits have become 350% more affordable, wine 270% and beer 170% (figure 3). The steep change came in the mid1990’s as a direct result of industry pressure; drinks became even cheaper and stronger and liver death rates escalated. Furthermore, over the course of the decade alcohol advertising expenditure increased by two thirds and the marketing focus shifted towards young people, with the introduction of alcopops, ‘vertical drinking’ pubs and alcohol sponsorship of music festivals; average alcohol consumption of 11-15 year children increased by two thirds and ‘Binge Britain’ was born. The HoC report outlined the abject failure of self regulatory codes to protect young people from alcohol marketing. Finland Finland has also seen profound changes in the previously very tight fiscal regulation of alcohol largely as a result of joining the EU. Finland was forced to withdraw its alcohol monopoly on the production, import, export and wholesale of alcohol upon entering the EU in 1995. Then in 2004, prior to neighbouring Estonia’s entry into the EU, Finland was forced to lower alcohol taxation to avoid significant loss to the national tax base. Whilst this move was prompted by fiscal rather than public health objectives, it would arguably never have happened had the EU not introduced lighter controls on imports for personal use. Consumption jumped by 10% in 2004 and alcohol-induced liver disease increased by 29% on the previous BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 19 year. Just like the UK, Finland has seen changes in the type of alcohol consumed, with a three-fold increase in wine consumption, a two-fold increase in beer consumption and a smaller 30% rise in spirits consumption since 1970. Given the relaxation in the previously relatively tough controls on alcohol in both countries it would be astonishing if liver deaths had not increased in the UK and Finland. But how can the marked fall in alcohol consumption and liver deaths in France and Italy be explained? Southern Europe The wine-producing countries of Southern Europe, with the exception of Greece, have recorded declining trends in alcohol consumption since the 1960’s - long before alcohol control measures were implemented. Total alcohol consumption in France has fallen by 12 litres per capita since the 1950s whilst the trend in Italy began later, dropping from 15.9 litres of pure alcohol per capita in 1970 to 6.9 litres in 2005. This drop was due to an overwhelming decrease in wine consumption, and is likely due a variety of factors which may be thought of in phases. Somewhat later than the connection of smoking to lung cancer, the link between cirrhosis and alcohol intake was only fully established in the 1960’s. As such, alcohol was not a major concern for institutions controlling public health or public order. Wine consumption in Italy was closely linked to rural lifestyles and rural-urban migration led to less wine drinking. Similar trends occurred in France. The move to urbanisation was the first phase, and was most active in the 1960’s and 70’s but consumption has continued to fall well into the 1990s and beyond - other factors were clearly also playing a part. Levels of wine production remained high in France and Italy. Measures taken by the European Commission in the late 1970s and early 1980s to reduce wine production and improve the quality of the product as part of the Common Agricultural Policy cannot alone account for the drop in internal consumption. Rather a move to quality of production was a reaction by the industry to consumer choice and reduced demand. The middle classes were the pioneers of change in France, with purchasing transferring to lower volume but higher quality options instead-“bottles with corks” as opposed to large plastic containers of very cheap wine (figure 4). This is good news for the wine industry and suggests that profitability and improved health can go hand in hand by moving towards quality and away from quantity – a lesson that UK supermarkets would do well to learn from their French and Italian counterparts. Perhaps another reason for change was that most people countries had a friend or relative suffering the health consequences of alcohol – something that has only really started in the UK more recently. Coupled with the health campaigns in both countries, the image of wine drinking wine was no longer as a source of health and happiness and did not conform to the emerging health consciousness trends. In terms of emerging trends in Italy, experts have identified the co-existence of two parallel alcohol consumption patterns: the traditional Mediterranean drinking pattern on the one hand, and a second pattern found among younger drinkers with 24% of 20-24 year-old Italians reporting binge drinking on occasion. In recent years alcoholic beverages have become more affordable for young Italians, with alcohol experts again noting an overt marketing strategy targeting young people. There has been an associated increase in the social harm from alcohol and the policy reaction has included local restrictions and bans on the sale of alcoholic beverages to minors and regulations aimed at decreasing the availability of alcohol in public places and at public events. Southern Europe is clearly not immune to northern tendencies. This trend is hidden within the general trend towards lower per capita consumption, but is starkly apparent when you look at patterns of consumption by age group. Discussion and implications for policy Despite increasing homogenisation of alcohol consumption in Europe, the trends in each of the four countries examined indicate that there are a number of different drivers that impact upon levels of alcohol- 20 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE attributable liver mortality. In northern Europe, a combination of primarily economic and market factors have contributed to increased levels of total consumption and its associated harm, whilst in southern Europe social changes and health awareness have contributed to the downward trend in alcohol-related liver deaths from previously very high levels. For many years mortality rates in Northern and Southern Europe looked to be converging, but have crossed over the trends are continuing. In the UK mortality rates and hospital admissions driven cheap alcohol continue to increase. Alcohol consumption in the WHO European Health Region remains the highest in the world and emerging trends, such as those seen among young people in Italy, mean that policy action needs to be taken to ensure that the decrease in liver cirrhosis is maintained. In global terms, Europe’s alcohol control policies are still not proportionate to the level of overall harm from alcohol. Taxation policy emerged as a crucial lever impacting upon alcohol consumption. In both the UK and Finland lower tax rates have helped to contribute to making alcohol more affordable. In an EU context the relaxation of restrictions in cross border trade has had very deleterious effects in terms of taxation, price and alcoholrelated ill health. The marketing activities of the alcohol industry and retailers have had a huge impact in young people. Self regulation in this respect has failed, and other mechanisms need to be explored. The UK House of Commons Health Committee has recommended a fully independent regulatory authority to control alcohol marketing, and the EU would do well to examine these proposals carefully. However the reduction in liver deaths in France has occurred alongside an increase in profitability of the wine industry as a result of the industry model shifting from one based on quantity (the current UK model) to one based on quality, and here the EU in the form of the common agricultural policy may have had a beneficial effect, driving down the amount of cheap alcohol that is produced in order to protect farmers. Given the tight relationship between death rates and consumption, a reduction on the overall %ABV of alcoholic beverages is another mechanism whereby consumption can be reduced but profitability of the wine industry maintained or indeed increased. For example wine at 8.5% ABV is taxed at the same level as wine at 14% ABV under EU law – a nonsensical system that benefits neither consumer nor industry. Current alcohol policy in Europe Alcohol policy in Europe has two streams, at member state level the picture is mixed. Some countries, notably France, have developed outstanding examples of inventive and effective evidence based alcohol policy, for example the Loi Evin which has protected young people from the marketing pressures of the drinks industry. Other countries, notably the UK, have effectively transferred large segments of alcohol policy to the vested interests of the drinks industry via the ‘Responsibility Deals’. These are bodies comprising representatives of the alcohol, food and retail industries which aim to introduce voluntary measures to curb alcohol related harm. This untested approach has drawn approbation from the health community in the UK who refused to sign the relevant agreements in 2010. The EU Commission alcohol strategy commenced in 2006, and has five priority areas: • Protect young people, children and the unborn child; • Reduce injuries and death from alcohol-related road accidents; • Prevent alcohol-related harm among adults and reduce the negative impact on the workplace; • Inform, educate and raise awareness on the impact of harmful and hazardous alcohol consumption, and on appropriate consumption patterns; • Develop and maintain a common evidence base at EU level. Political imperatives and the subsidiarity of EU taxation has meant that the Commission has also been heavily reliant on voluntary actions and self regulation by the drinks industry despite the evidence that such BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 21 approaches are ineffective on the whole(4). The alcohol strategy has a number of components including the EU Alcohol Forum, which again brings health and industry representatives together in a forum for action. The EU liver community has been an active member of this forum via EASL and the RCP although other than a promising work stream on the monitoring of marketing communications, hard outcomes have been few and far between. In 2011 the EU alcohol strategy will need to be renewed, initial soundings from the Commissioner for Health were not promising, but a recent meeting of member states offered unanimous support for a new alcohol strategy which will be informed by an independent evaluation of the previous five years work. The support of EASL and the EU liver community will be vital over the next year or so as this process moves forward. The simple truth is that of the 200,000 alcohol related deaths in the EU every year, much due to liver disease, probably around two thirds are preventable if each country adopted effective policies to reduce alcohol related harm. The question for the liver community is: “how big is our ambition to tackle liver mortality and are we prepared to be advocates for the measures needed to achieve it?”. Relationship between liver death rates and population level alcohol consumption Figure 1 The relationship between standard liver death rates (per 100,000) and overall alcohol consumption (pure alcohol litres per capita, age 15+) in the 4 countries in the EU (pre 2004) with the largest rises or falls in liver deaths between 1970 and 2008. Data is from the World Health Organisation, European Health for All database (HFA-DB): http://data.euro.who.int/hfadb/ 22 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 23 Trends in liver death rates in the four EU countries which have seen the largest changes since 1970 Figure 2 Trends in Finland, France Italy, UK and the EU (pre 2004) overall in standard liver death rates (under the age of 65) over time between 1970 and 2008. Data is from the World Health Organisation, European Health for All database (HFA-DB): Liver death rates and the shift from table wine to higher quality wine consumption in France Figure 4 Liver death rates in France have fallen as overall wine consumption has fallen. But the overall real value of wine production has increased, as a result of the huge shift in wine production from table wines to higher quality wine produced in specific regions (PSR) together with appropriate marketing by the French wine industry. Affect of duty changes on the affordability of different types of alcoholic beverage in the UK, strong drink has become relatively cheaper. Figure 3 The graph shows how income inflation has affected the levels of duty on various alcoholic beverages since 1980. Trends in the duty on various alcoholic beverages were adjusted for changes in real disposable income – using a methodology developed by the NHS Information Centre (Statistics on Alcohol 2008, Appx A p95-96) to calculate an Alcohol Affordability Index. The Beverage Duty Affordability Index – is normalised to 100% in 1980. It was calculated as follows - using spirits as an example: Spirits Duty Index (SDI) = spirits duty normalised to 1980 Relative Spirits Duty Index (RSDI) = SDI / Retail Price Index (RPI) x100 Spirits Duty Affordibility Index SDAI = Real Disposable Income (RDI) / RSDI x 100 Beverage duty data were from the Beer and Pub Assocaition Handbook 2008, pages 50-52. RPI and RDI were from Statistcis on Alcohol 2008 Table 5.3 Wine consumption data and liver death rate are given in comparison with the year 2000. Wine value is the value of total wine production given in European Union Purchasing Power Standard (PPS) – exports increased from 12% to 31% over the same period. Data are from Eurostat (http://epp.eurostat.ec.europa. eu) and the WHO Statistical Information System (http://www.who.int/whosis). 24 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Dr Nick Sheron is the Royal College of Physicians representative at the EU Alcohol Forum and parts of this article are reproduced with kind permission of the RCP Journal Clinical Medicine(5). REFERENCES World Health Organisation. Global status report on alcohol and health 2011. Anderson P, Baumberg B. Alcohol in Europe: A public health perspective. EU Health and Consumer Protection Directorate General; 2007. House of Commons Health Committee. Alcohol: First Report of Session 2009–10. London: Stationary Office; 2010 Jan 8. Babor TF, Caetano R, Casswell S, Edwards G, Giesbrecht N, Graham K, et al. Alcohol: No Ordinary Commodity—Research and Public Policy Oxford and London: Oxford University Press, 2003. Jewell J, Sheron N. Trends in European liver death rates: implications for alcohol policy. Clin Med 2010 Jun;10(3):259-263. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 25 PATTERNS OF ALCOHOL INTAKE AND ALD: EFFECTS OF BINGE DRINKING ON THE LIVER Sam Zakhari Bethesda, Maryland, USA E-mail: [email protected] KEY POINTS • Binge drinking (too much too fast ) is a pattern corresponds to consuming 5 or more drinks (male), or 4 or more drinks (female), in about 2 hours. • Binge drinking while fasting may result in hypoglycemia and severe lactic acidosis. • Binge drinking may precipitate acute severe alcoholic hepatitis (AH) against a background of chronic liver disease. Thirty day mortality in patients with severe AH may exceed 40%. • If you drink, drink moderately with food. PATTERN OF DRINKING In the United States, the pattern of drinking is divided into three categories: moderate, low-risk, and high risk. • Moderate drinking, according to the U.S. dietary guidelines, is up to 2 drinks per day for men and up to 1 drink per day for women. Obviously, the definition of moderate drinking varies in different countries. • Low-risk drinking is not just another term for "moderate" drinking, even though the weekly amounts may be the same, but the daily ones are different; the recommendations serve different purposes for different types of drinkers. Low-risk drinking for healthy men under age 65 is no more than 4 drinks on any day and 14 per week, and for healthy women (and men over 65) is no more than 3 drinks on any day and 7 per week. • High-risk drinking comprises: 1) binge drinking (too much too fast - A “binge” is a pattern of drinking alcohol that brings blood alcohol concentration (BAC) to 0.08 gram percent or above. For the typical adult, this pattern corresponds to consuming 5 or more drinks (male), or 4 or more drinks (female), in about 2 hours; and 2) chronic heavy drinking (drinking too much too often). BINGE DRINKING AND THE LIVER While drinking too much and too often over a long period of time results in alcoholic liver disease (ALD), which encompasses fatty liver, steatohepatitis, liver fibrosis and cirrhosis, and may proceed to hepatocellular carcinoma, binge drinking can lead to glycogen depletion, which would be aggravated in the presence of liver disease, and may lead to acidosis and hypoglycemia. In addition, people who drink heavily tend to have hyperuricemia and hypertriglyceridemia, which may exacerbate diabetic hypertriglyceridemia. Correlation of Quantity and Frequency of Drinking and Liver Damage: The effects of drinking too much too fast, or too much too often on the liver have been sparingly studied. Past studies focused on the incidence of cirrhosis among alcoholics (Lelbach et al., 1975), or sought the clinical manifestations of alcoholism among cirrhotic patients (Caroli et al.,). In these two approaches, the quantity of alcohol consumed and the drinking pattern were undetermined. A third indirect approach attempted to correlate average quantities of alcohol consumption (based on demographic and economic statistics) with cirrhosis mortality. This approach, however, did not measure the quantity and frequency of alcohol consumption, and did not provide information on individual consumption and risk. In a prospective study, Kamper-Jørgensen and colleagues (2004) interviewed a cohort of 6152 alcoholabusing men and women about their drinking pattern, frequency of alcohol intake, duration of alcohol misuse, and beverage type. The rate of alcoholic cirrhosis mortality in men and women was, respectively, 27- and 35-fold the rate of the Danish general population. They also reported that “alcohol has a threshold effect rather than a dose-response effect on mortality from alcoholic cirrhosis.” 26 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE This is not surprising since their lowest tier of drinking comprised an average of 5-9 drinks per day, which is already in the heavy drinking category. Analysis of quantity consumed and drinking patterns of an Italian population showed that consuming 30 g/day is the minimum quantity to induce measurable risk of developing cirrhosis in men and women (Bellentani et al., 1997). Drinking without food, independent of the quantity, was associated with an increased prevalence of alcoholic liver disease. A meta-analysis of alcohol consumption and risk of various diseases, including cirrhosis and cancer, reported an increased risk as alcohol consumption increased from 25 g/day (2 drinks) to 100 g/day (8 drinks) (Corrao et al., 2004). Alcohol Metabolism and Liver Damage: Although alcohol metabolism is often considered the predominant factor in causing alcohol-associated liver damage, other factors such as inflammatory cytokines, immunologic and metabolic pathways derangements, effects on signal transduction, proteasome inhibition, increased gut leakiness, etc contribute to ALD. Ingested ethanol is readily absorbed from the gastrointestinal tract. Only about 2-10% of the absorbed alcohol is eliminated via the lungs and kidneys; the remaining 90% is metabolized mainly by oxidative pathways in the liver and by non-oxidative pathways in extrahepatic tissues. Oxidative metabolism in the liver results in extensive displacement of the liver’s normal metabolic substrates, the production of acetaldehyde and ROS, and an increase in the NADH/NAD+ ratio (Figure 1). The major pathway of oxidative metabolism of ethanol in the liver involves multiple isoforms of cytosolic alcohol dehydrogenase (ADH), which results in the production of acetaldehyde. Accumulation of this highly reactive and toxic molecule contributes to liver damage. The oxidation of ethanol is accompanied by the reduction of NAD+ to NADH and, thereby, generates a highly reduced cytosolic environment in hepatocytes. The cytochrome P450 isozymes, including CYP2E1, 1A2 and 3A4, which are predominantly localized to the ER, also contribute to ethanol’s oxidation to acetaldehyde in the liver, particularly after chronic ethanol intake. CYP2E1 is induced by chronic ethanol consumption and assumes an important role in metabolizing ethanol to acetaldehyde at elevated alcohol concentration. It also produces highly reactive oxygen species (ROS), including hydroxyethyl, superoxide anion, and hydroxyl radicals. Another enzyme, catalase, located in peroxisomes, is capable of oxidizing ethanol in vitro in the presence of a hydrogen peroxide (H2O2)generating system, such as NADPH oxidase or xanthine oxidase, or during peroxysomal oxidation of very long-chain fatty acids. Quantitatively, however, this is considered a minor pathway of ethanol oxidation. Acetaldehyde, produced by ethanol oxidation through any of these mechanisms, is rapidly metabolized mainly by mitochondrial aldehyde dehydrogenase (ALDH2) to form acetate and NADH. Mitochondrial NADH is re-oxidized by the electron transport chain. Most of the acetate resulting from ethanol metabolism escapes the liver to the blood and is eventually metabolized to CO2 by way of the tricarboxylic acid (TCA) cycle in cells with mitochondria capable of converting acetate to the metabolically active intermediate acetyl-CoA. This occurs primarily in tissues such as heart, skeletal muscle and brain. Consequences of Alcohol Metabolism by Oxidative Pathways The following effects (Figure 1, refer to symbols 1-2-3-4) result from alcohol metabolism in the liver, which may contribute to various degrees to liver damage: a) Acetaldehyde generation/adduct formation: If acetaldehyde, produced by the oxidation of alcohol, accumulates to high concentrations, it can form adducts with DNA and RNA, and decrease DNA repair. Acetaldehyde also has the capacity to react with lysine residues on proteins including enzymes, microsomal proteins, microtubules, and affect their function. Formation of protein adducts in hepatocytes may contribute to impaired protein secretion, resulting in hepatomegaly. In addition, there is evidence that acetaldehyde and malondialdehyde (a by-product of lipid peroxidation) can combine and react with lysine residues on proteins, giving rise to stable malondialdehyde-acetaldehyde (MAA)-protein adducts that can be immunogenic and, thus, can contribute to immune-mediated liver damage. Also, MAA adducts have proinflammatory and profibrogenic properties. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 27 b)Change in Hepatocyte Redox State (Increase in NADH/NAD+ Ratio): It has been demonstrated more than 50 years ago that both acute and chronic alcohol consumption shift the redox state of the liver to a more reduced level (e.g., Smith and Newman, 1959; Rawat, 1968), similar to but more pronounced than the shift observed in diabetes and during starvation. Alcohol metabolism produces a significant increase in the hepatic NADH/NAD+ ratio in both the cytosol and the mitochondria, as evidenced by an increase in the lactate/pyruvate and β-hydroxybutyrate/acetoacetate ratios, respectively (Cunningham and Bailey, 2001). Thus, ethanol oxidation vastly increases the availability of oxidizable NADH to the electron transport chain in the mitochondria. The liver responds to ethanol exposure in part by increasing the rate of oxygen uptake, which may lead to periods of hypoxia, particularly in the downstream (pericentral) parts of the liver lobule. c)Formation of reactive oxygen species (ROS), reactive nitrogen species (RNS), and oxidative stress: Hepatic mitochondria produce ROS through the activity of the electron transport chain (ETC) as a by-product of oxidative phosphorylation. Normally, a small fraction of electrons entering the ETC can prematurely escape from complexes I and III and directly react with 1-3 % of respiratory oxygen molecules to generate the superoxide anion radical, which is then dismutated by the mitochondrial manganese superoxide dismutase (MnSOD) into hydrogen peroxide (H2O2). Mitochondrial glutathione peroxidase (GPx) then converts H2O2 into water by using reduced glutathione (GSH) as a cofactor. Thus, most of the ROS generated by the ETC in the normal state are detoxified by the mitochondrial antioxidant defenses. The non-detoxified portion of ROS diffuses out of mitochondria, and affects signal transduction pathways and gene expression, triggering cytokines, hormones, and growth factors, which if excessive may lead to hepatic inflammation, necrosis, and/or apoptosis. In addition, metals (e.g., iron and copper) can further react with H2O2 to produce hydroxyl radicals via the Fenton reaction Nitric oxide (NO), a reactive nitrogen species critical for hepatocyte biology, can interact with peroxides to generate peroxynitrite (ONOO-), which, depending on the amount and duration, could be detrimental to the liver. NO is produced by iNOS from L-arginine and oxygen in combination with electrons from NADPH and cofactors such as FAD and FMN. iNOS is expressed in all liver cells (i.e., hepatocytes, Stellate cells, Kupffer cells, and vascular endothelial cells) and its expression is induced by IL-1β alone or in combination with TNF-α, IFNγ, and/or LPS. Ethanol-induced oxidative stress has been attributed to a decrease in the NAD+:NADH ratio, acetaldehyde formation, CYP2E1 induction, hypoxia, cytokine signaling, mitochondrial damage, LPS activation of Kupffer cells, reduction in antioxidants particularly mitochondrial and cytosolic glutathione, one electron oxidation of ethanol to 1-hydroxy ethyl radical, and the conversion of xanthine dehydrogenase to xanthine oxidase. d)Formation of acetate The increase in mitochondrial NADH in hepatocytes due to acetaldehyde metabolism contributes to the saturation of NADH dehydrogenase, thus hampering the function of the tricarboxylic acid (TCA) cycle. Liver mitochondria have a limited capacity to oxidize acetate to CO2 in the TCA cycle because acetyl CoA synthase 2, a mitochondrial enzyme involved in the oxidation of acetate is absent from the liver, but abundant in heart and skeletal muscles (Fujino et al., 2001). Thus, most of the acetate resulting from ethanol metabolism escapes the liver into the blood circulation and is eventually metabolized to CO2 by way of the TCA cycle in cells with mitochondria that contain enzymes to convert acetate to acetyl CoA, such as heart, skeletal muscle and brain. During ethanol metabolism, when circulating ethanol is in the mM range, acetaldehyde is in the :M range, and acetate is in the mM range. 28 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Figure 1 BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 29 Ethanol indirectly increases oxygen use by hepatocytes through lipopolysaccharide-induced activation of Kupffer cells, resulting in the release of prostaglandin E2 and stimulation of hepatocyte metabolic activity, further contributing to the onset of hypoxia. Binge drinkers have could have severe hypoxia and hepatic reperfusion injury (French, 2004). ALCOHOLIC LIVER DISEASE (ALD) The disease profiles associated with chronic alcohol consumption show a great deal of individual variability in severity and progression for comparable levels of alcohol consumption. It has traditionally been assumed that this variability may reflect individual genetic factors, such as the expression and activity of individual isoforms of the alcohol-metabolizing enzymes ADH and ALDH, but is also influenced by variations in temporal intake patterns (binge vs chronic drinking), nutritional status, gender, exposure to other damaging factors such as smoking, or use of other drugs of abuse. In addition, the onset and severity of alcoholic liver disease is strongly influenced by other comorbid conditions such as obesity or HCV infection. The origin of this increase in susceptibility to alcoholic liver disease is not due solely to intrahepatic factors, but may also involve alcohol-induced changes in other tissues, ranging from adipose tissue to the CNS, the gut, and the immune system. Thus, although the factors contributing to alcohol-induced liver disease remain poorly understood, they are complex and systemic. Figure 2 Figure 1. ADH = Alcohol d ehydrogenase; ALDH = Aldehyde dehydrogenase; NAD = Nicotinamide adenine dinucleotide; NADH = reduced NAD; NADP = Nicotinamide adenine dinucleotide phosphate; H2O2 = Hydrogen peroxide. CONSEQUENCES OF INCREASED NADH/NAD+ RATIO: Increased NADH/NAD+ ratios in both the cytosol and mitochondria of hepatocytes influence the direction of several reversible reactions leading to alterations in hepatic lipid, carbohydrate, protein, lactate, and uric acid metabolism. These changes happen after binge drinking, and seem to be attenuated with chronic ethanol ingestion. 1.Alcoholic hypoglycemia. The increase in NADH due to alcohol metabolism prevents pyruvate conversion to glucose by lowering the concentration of pyruvate, which in turn decreases the pyruvate carboxylase reaction, one of the rate limiting steps of gluconeogenesis (Krebs et al., 1969). Collectively, this could result in clinically significant hypoglycemia. 2.Alcoholic acidosis. Ketoacidosis is common in chronically malnourished alcoholics, and is due to the formation of ketone bodies, primarily β-hydroxybutyrate (Gauthier et al., 2002). In addition, the increase in NADH favors the conversion of pyruvate to lactate, resulting in lactic acidosis. Binge drinkers may present with severe acidosis with relatively low ketone bodies and hypoglycemia. The increase in NADH/NAD+ ratio diminishes pyruvate dehydrogenase (PDH) activity in the mitochondria, resulting in diminished conversion of pyruvate to acetyl CoA. PDH activity is further diminished in chronic alcoholics due to hypomagnesemia and thiamine deficiency, resulting in the inhibition of pyruvate utilization in the TCA cycle. 3. Hyperuricemia. Patients who drink too much frequently may develop hyperuricemia because lactate and ketone bodies formed after alcohol metabolism compete with urate for excretion in the distal tubules of the kidney (Yamanaka, 1996). Alcohol metabolism also releases the ATP degradation products, hypoxanthine and adenosine which enter the purine nucleotide degradation pathway, resulting in increased formation of urate. 4.Hypertriglyceridemia. Heavy alcohol consumption increases the synthesis of triglycerides, resulting in fatty liver and hypertriglyceridemia, and may exacerbate diabetic hypertriglyceridemia. The increase in NADH/NAD+ ratio results in an increase in v-glycerophosphate, which favors hepatic triglyceride accumulation, and also inhibits mitochondrial β-oxidation of fatty acids (Lieber, 1984). 5.Hypoxia. Metabolism of ethanol by hepatocytes tends to increase oxygen uptake, resulting in significant hypoxia in the perivenous hepatocytes, the site of early liver damage due to chronic alcohol consumption. As shown in Figure 2, ALD includes a broad range of defects that vary considerably in severity, including: a)Fatty liver (hepatic steatosis) histologically characterized by the occurrence of lipid droplets in hepatocytes. This condition is long thought to be a relatively innocuous side effect of heavy drinking, because it is usually readily reversible upon cessation of alcohol consumption. b)Alcoholic hepatitis, an inflammatory condition characterized by significantly increased serum levels of liver enzymes (ALT and AST) and moderate to severe tissue damage, including necrotic foci with neutrophil infiltration. c)Liver fibrosis/cirrhosis, a modest (10-15%) fraction of chronic heavy drinkers proceeds to develop fibrosis and cirrhosis. d)Hepatocellular carcinomas occur in about 2% of cirrhotic patients. 30 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE The factors that facilitate the development of hepatitis and cirrhosis are not well characterized. However, impairment in the cellular stress defense mechanisms, (e.g. oxidative stress) (Fernandez-Checa and Kaplowitz, 2005), or derailment of the balance of autocrine or paracrine mediators that are critical in maintaining normal homeostatic conditions are documented. In addition, chronic alcohol consumption is known to interfere with liver regeneration, which under normal conditions is a highly effective repair mechanism unique to the liver that avoids scar tissue formation. REFERENCES Adachi M, Ishii H (2009) Hyperadiponectinemia in alcoholic liver disease: friend or foe? J Gastroenterol Hepatol 24:507-8. Arteel GE (2008) New role of plasminogen activator inhibitor-1 in alcohol-induced liver injury. J Gastroenterol Hepatol 23(Suppl 1):S54-9. Basra G, Basra S, Parupudi S. Symptoms and signs of acute alcoholic hepatitis. World J Hepatol. 2011; 3:118-20. Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. Gut 1997;41:845-850. Caroli J, Mainguet P, Ricordeau P, Foures A. L’importance de la laparoscopie dans la classification anatomo-clinique des cirrhoses du foie. Cirrhose alcoolique et nutritionnelle XXXIIe congres français. Corrao G, Bagnardi V, Zambon A, La Vecchia C. A meta-analysis of alcohol consumption and the risk of 15 diseases. Prev Med 2004;38:613-619. Cunningham CC, Bailey SM (2001) Ethanol consumption and liver mitochondria function. Biol Signals Recept 10:271-82. Fernandez-Checa JC, Kaplowitz N (2005) Hepatic mitochondrial glutathione: transport and role in disease and toxicity. Toxicol Appl Pharmacol 204:263-73. French SW. The role of hypoxia in the pathogenesis of alcoholic liver disease. Hepathol Res 2004;29:69-74. Fujino T, Kondo J, Ishikawa M, Morikawa K, Yamamoto TT. Acetyl-CoA synthase 2, a mitochondrial matrix enzyme envolved in the oxidation of acetate. JBC, 2001, 276:11420-11426 Gauthier PM, Szerlip HM. Metabolic acidosis in the intensive care unit. Crit. Care Clin. 18:289-308, 2002. Hoek JB, Cahill A, Pastorino JG (2002) Alcohol and mitochondria: a dysfunctional relationship. Gastroenterology 122:2049-63. Holmuhamedov E, Lemasters JJ (2009) Ethanol exposure decreases mitochondrial outer membrane permeability in cultured rat hepatocytes. Arch Biochem Biophys 481:226-33. Kamper-Jorgensen M, Gronbaek M, Tolstrup J, Becker U. Alcohol and cirrhosis: dose--response or threshold effect? J Hepatol 2004;41:25-30. Kaplowitz N, Than TA, Shinohara M, Ji C (2007) Endoplasmic reticulum stress and liver injury. Semin Liver Dis 27:367-77. Krebs HA, Freedland RA, Hems R, Stubbs M. Inhibition of hepatic gluconeogenesis by ethanol. Biochem J 1969;112:117-124. Lelbach WK. Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Ann N Y Acad Sci 1975;252:85-105. Lieber CS. Alcohol and the liver: 1984 update. Hepatology, 4:1243-1260, 1984. Rawat AK (1968) Effects of ethanol infusion on the redox state and metabolite levels in rat liver in vivo. Eur J Biochem 6:585-92. Nieto N, Rojkind M. Repeated whiskey binges promote liver injury in rats fed a cholinedeficient diet. J Hepatol. 2007; 46:330-9. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 31 O’Shea RS, Dasarathy S. McCullough AJ. Alcoholic Liver Disease. Hepatology. 2010; 51:307-28. Smith ME, Newman HW (1959) The rate of ethanol metabolism in fed and fasting animals. J Biol Chem 234:1544-9. Yamanaka H. Alcohol ingestion and hyperuricemia. Nippon Rinsho, 54:3369-73, 1996. You M, Considine RV, Leone TC, Kelly DP, Crabb DW (2005) Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology 42:568-77. You M, Liang X, Ajmo JM, Ness GC (2008) Involvement of mammalian sirtuin 1 in the action of ethanol in the liver. Am J Physiol Gastrointest Liver Physiol 294:G892-8. Zakhari S. Overview: how is alcohol metabolized by the body? Alcohol Res Health. 2006; 29: 245-54. Review. Zakhari S, Li TK. Determinants of alcohol use and abuse: Impact of quantity and frequency patterns on liver disease. Hepatology. 2007,46:2032-9. Review. 32 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE NATURAL HISTORY OF ALD: ROLE OF ENVIRONMENTAL AND GENETIC FACTORS Felix Stickel Bern, Switzerland E-mail: [email protected] BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 33 Studies in humans estimate that liver steatosis evolves in literally all excessive drinkers, complicated by significant necroinflammation and fibrosis in only approximately one third, while 10% progress to cirrhosis (1). Among the latter, 1-2% of patients per year develop hepatocellular carcinoma (HCC) as a severe complication (2). This variable natural course is believed to derive from a complex interplay between environmental and host risk factors (Figure 2). Figure 2 KEY POINTS • Alcoholic liver disease is a complex disease in which environmental and host factors modulate evolution and progression of liver damage. • Confirmed risk environmental factors for progressive ALD include quantities of alcohol, obesity, and chronic coinfection with hepatitis viruses (B and C). • Strong evidence supporting genetic background as an important modulator of susceptibility for ALD. • Lack of evidence for a role of HFE mutations in progression of ALD. • Heterozygous and homozygous carriage of PNPLA3 rs738409 (G) allele is the first confirmed genetic risk factor for ALD. INTRODUCTION Alcoholic liver disease (ALD) is a complex disease and accounts for the majority of chronic liver diseases in Western countries. Development of ALD depends on long-term excessive drinking and other environmental, individually acquired, and inherent modifying factors which interact over time to allow for or prevent ALD development and progression (Figure 1). While many environmental factors are now well-characterized by population-based and epidemiology studies, recent advances in our understanding of the role of genetic variation in the phenotypic expression of diseases in man precipitated research activities for host genetic factors that influence the course of many complex diseases, including ALD. Figure 1 Non-genetic vs. genetic determinants of ALD progression Risk factors for the development of progressive alcoholic fibrosis are commonly stratified into host (including genetics) or environmental (non-genetic) modifiers. Crucial environmental factors that modulate the development of ALD are the quantity of alcohol over time, the continuity of its abuse, and drinking patterns, while gender, ethnic descent, co-existing metabolic syndrome or chronic viral hepatitis, and iron overload are important host factors. Obviously, the most crucial environmental factor is alcohol per se, displaying a clear dose-relationship between the amount of alcohol and the likelihood of developing alcoholic cirrhosis (Figure 3). Crosssectional studies have shown that alcoholic steatosis is encountered in approximately 60% of subjects who drink >60g/day, and the risk of developing cirrhosis highest among those with a consumption of >120g/day (1). In a meta-analysis, the risk of developing cirrhosis increased exponentially with a daily consumption from 25g to 100g (3). Figure 3 Unlike many other chronic liver diseases, ALD is a potentially avoidable disease since ALD does not develop unless alcohol is consumed excessively. Thus, ALD only evolves if interventions against harmful drinking do not take place, or fail. However, scientific and common cognition show that alcohol consumption per se is not necessarily sufficient to elicit significant ALD since only a minority of heavy drinkers progresses to severe ALD. 34 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Whether the type of alcoholic drink consumed, e.g. wine as opposed to beer or hard liquor, impacts the risk of ALD is still controversial, however, consensus among scientists exists that it is the content of pure alcohol that likely outweighs all other constituents in different drinks that may potentially modulate the biological effects of alcohol. Patterns of drinking vary substantially among patients with ALD and may influence the risk of ALD. There are conflicting data on this issue, but several recent studies comparing daily vs. binge drinkers showed that the former had a higher risk of cirrhosis (4). However, it is worrisome that countries with a high prevalence of binge-drinking, such as the UK, reveal a marked increase of cirrhosis mortality per year of 3.4 in 1957-61 to 14.1/100.000 in 1997-2001 which may rather reflect a rising incidence of harmful drinking predicting long-term alcohol abuse (5). BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 35 GENETIC VARIANTS ASSOCIATED WITH ALD In the search for genetic risk factors for ALD tremendous work has been afforded, however, most investigated genetic variants were not confirmed in independent case control studies. If commonly accepted quality criteria for candidate gene case control studies are applied, only few studies bear a certain degree of scrutiny, as many of them are hampered by one or several limitations as outlined in table 1. An unequivocal risk factor for fibrosis progression in ALD is obesity, with numerous studies demonstrating that overweight is the most important single risk factor of cirrhosis and necroinflammation in heavy drinkers (6). The synergy between obesity and heavy alcohol intake presumably reflects similar mechanisms of disease for both ALD and non-alcoholic fatty liver disease, such as increased oxidative stress via induction of CYP450 2E1, upregulated secretion of proinflammatory cytokines from adipose tissue, and an expanded mass of adipose tissue secreting profibrogenic factors such as noradrenaline, angiotensin II and leptin in combination with low levels of adiponectin. Numerous case-control, cross-sectional, and cohort studies have unequivocally shown that co-existence of alcohol misuse and chronic hepatitis C virus infection significantly increases the risk of developing cirrhosis (7). Together, these data show that individuals with chronic hepatitis C who drink more than 40g per day increase their risk of developing cirrhosis approximately 4-fold. HOST GENETICS AND RISK OF ALD Three lines of evidence suggest an at least partial genetic background of the ALD phenotype: 1. Women are more susceptible for ALD when exposed to similar amounts of alcohol; 2. Hispanics are more prone to developing ALD than Blacks and Whites; 3. Twin studies demonstrate that monozygotic twins have a higher prevalence of alcoholic cirrhosis than dizygotic twins. Gender-specific susceptibility towards alcohol has been recognized for long. Studies in humans have demonstrated that women are more susceptible towards the hepatotoxic effects of alcohol, and develop ALD more quickly with equal amounts of daily alcohol consumption than men (8). The pathophysiology behind this increased sensitivity to alcohol is not yet fully understood but could be – among other factors – related to hormonal differences such as estrogens and their synergistic impact on oxidative stress and inflammation. Gender-related metabolic differences also exist, and women drinking equal amounts of alcohol reveal higher blood ethanol levels than men due to higher gastric alcohol dehydrogenase levels resulting in a faster first-pass metabolism of alcohol in men, or to a lower volume of distribution for alcohol in women compared to men. Different ethnic groups reveal notable differences in the prevalence of ALD and associated mortality. However, such seemingly ethnic differences in rates of alcoholic cirrhosis and ALD could also be related to the amount and type of alcohol consumed, dietary traditions, differences in socioeconomic status, access to medical care, and/or differences in attitudes towards a healthy life style. The identification of the genetic background of iron overload by detection of mutations within the hemochromatosis (HFE) gene gave rise to the hypothesis whether their presence may also affect iron storage in alcohol abusers. However, genetic case control studies with adequate matching of cases and controls for age, sex, and alcohol consumption detected no increased prevalence of HFE mutations in alcoholics with liver disease including cirrhosis (9). While genetic variation of the ADH, ALDH and GABA system have been consistently found associated with alcohol dependence, this risk is not further conveyed to developing ALD. In fact, only two candidate gene polymorphisms reveal sufficient data to consider them highly suspicious as genetic risk factors for ALD. 36 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE These are TNFα -238A (10) and PNPLA3 rs738409, of which only the latter is supported by robust and unequivocal data (Table 2). Together, data on PNPLA3 allow for the conclusion that PNPLA3 rs738409 GG carriers represent a genetically defined subpopulation of high risk subjects susceptible to progression of clinically inapparent to overt ALD. Whether PNPLA3 genotype represents a marker that will assist decisionmaking in clinical practice remains to be shown, as well as whether it could serve as a therapeutic target. Table 2 THE INTERNATIONAL LIVER CONGRESSTM 2012 37 However, still lacking are data from genome-wide analyses in ALD patients similar to what has been carried out in other chronic liver diseases. Conducting this kind of global scan would not only help to confirm PNPLA3 rs738409 as an important susceptibility marker of ALD, but also potentially identify novel, yet unkown genetic variants for better screening of patients, and subsequent clinical and experimental research. Despite the noted limitations, functional pathway information and the genetic risk factors of ALD start to converge into a common etiopathogenetic concept allowing for a better understanding of this serious disorder in the future. REFERENCES Study Design Patients Results Tian et al. * Genetic case control 482 cases (alcoholic cirrhosis) (Mestizo subjects with strong ethnic heterogeneity) 482 cases (alcoholic cirrhosis) 434 non-cirrhotic ALD 305 alcoholics w/o liver enzyme elevations rs738409 GG associated with cirrhosis when compared to controls (OR 2.25, 1.742.9; 1.7 x 10-10) and to non-cirrhotic ALD (OR 1.43, 1.15-1.78, 1.0 x 10-3) Association robust after ancestry correction (OR 1.81, 1.36-2.41; 4.7 x 10-5) Seth et al. * Genetic case control (British Caucasians) 266 cases (alcoholic cirrhosis) 182 controls (heavy drinkers w/o clinical ALD) rs738409 G homozygosity associated with alcoholic cirrhosis (OR 7.34, 2.19-24.52, p=0.0012) Carriage of rs738409 G allele associated with alcoholic cirrhosis (OR 1.95, 1.342.84, p=0.00002) Trépo et al. * Genetic case control (Belgium Caucasians) 330 cases (97% biopsyproven ALD; 263 cirrhotics) 328 controls (healthy individuals without ALD) rs738409 G associated with ALD (OR 1.54; 1.12-2.11, p=0.008) and alcoholic cirrhosis (OR 2.08; 1.15-3.77, p=0.02) PNPLA mRNA expression inversely correlated with cirrhosis and portal pressure Stickel et al. * Genetic case control (German Caucasians) Multicenter sample with 1,043 alcoholics (210 cirrhosis, 394 non-cirrhotic ALD, 439 alcoholic controls Population-based sample with 376 alcoholics (269 noncirrhotic ALD, 107 alcoholic controls) Non-alcoholic healthy subjects (n=162) Genotype rs738409 GG associated with alcoholic cirrhosis (OR 2.79, 1.55-5.04, p=1.18 x 10-5, cirrhosis vs. controls) Genotype rs738409 GG associated with alanine aminotransferase elevation (OR 2.33, 1.27-4.26, p=0.0085) Confirmation of association in separate replication sample (OR 4.75, 1.08-20.9, p=0.04, ALD vs alcoholic controls) Population-attributable risk of rs738409 to cirrhosis 26.6% * For full reference, please see ref. 11. Bellentani S, Saccoccio G, Costa G, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. Gut 1997;41:845-850. Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors. Gastroenterology 2004;127(5 Suppl 1):S35-50. Corrao G, Bagnardi V, Zambon A, La Vecchia C. A meta-analysis of alcohol consumption and the risk of 15 diseases. Prev Med 2004;38:613-619. Stokkeland K, Hilm G, Spak F, et al. Different drinking patterns for women and men with alcohol dependence with and without alcoholic cirrhosis. Alcohol Alcohol 2008;43:39-45. Mathurin P, Deltenre P. Effect of binge drinking on the liver: an alarming public health issue? Gut 2009;58:613-17. Raynard B, Balian A, Fallik D, et al. Risk factors of fibrosis in alcohol-induced liver disease. Hepatology 2002;35:635-8. Monto A, Patel K, Bostrom A, et al. Risks of a range of alcohol intake on hepatitis C-related fibrosis. Hepatology 2004;39:826-34. Sato N, Lindros KO, Baraona E, et al. Sex difference in alcohol-related organ injury. Alcohol Clin Exp Res 2001;25:40S-45S. Gleeson D, Evans S, Bradley M, et al. HFE genotypes in decompensated alcoholic liver disease: phenotypic expression and comparison with heavy drinking and with normal controls. Am J Gastroenterol 2006;101:304-10. Marcos M, Gómez-Munuera M, Pastor I, et al. Tumor necrosis factor polymorphisms and alcoholic liver disease: a HuGE review and meta-analysis. Am J Epidemiol 2009; 170:948-56. Stickel F, Hampe J. Genetic determinants of alcoholic liver disease. Gut 2012;61:150-9. 38 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE NOVEL MECHANISMS OF ALCOHOLIC STEATOHEPATITIS Sophie Lotersztajn Créteil, France E-mail: [email protected] KEY POINTS • The clinical spectrum of alcoholic liver disease includes steatosis, alcoholic hepatitis, fibrosis, cirrhosis and increased risk of hepatocellular carcinoma. • Steatosis results from alterations of lipid metabolism driven by alcohol, including: (i) increased delivery of free fatty acids in the liver originating from the adipose tissue (ii) enhanced de novo hepatic synthesis of fatty acids and reduced fatty acid β-oxidation and (iii) reduced fat export from the liver. • Ethanol, ethanol metabolites and oxidative stress play a major role in alcohol-induced hepatocellular injury. In addition, alcohol increases endotoxin levels that activate Kupffer cells, initiating an inflammatory process that leads to massive inflammatory cell recruitment, contributing to hepatocellular injury and fat accumulation. • Newly identified promising strategies mainly focus on modulation of gut microbiota and reduction of the inflammatory response (CXC chemokines, interleukin 17, the complement system), while sparing liver regeneration. Promising targets include the receptors for endocannabinoids (CB1 and CB2), sirtuin activators, and adenosine receptors. INTRODUCTION Alcoholic liver disease is characterized by a broad histological spectrum that encompasses isolated fatty liver (steatosis), steatohepatitis, fibrosis and ultimately cirrhosis (1). Fatty liver is the prevalent lesion foun in 90 % of excessive drinkers, and has long been considered innocuous. However, fat generates inflammatory signals and reactive oxygen species that initiate progression to more severe forms of the disease. Alcoholic steatosis is defined by the presence of fat droplets in hepatocytes and is the earliest response of the liver to chronic alcohol abuse. Environmental and genetic factors, and comorbid conditions (viral hepatitis, obesity, HIV…) accelerate progression to steatohepatitis, that occurs in about 20-40% of heavy drinkers. Steatohepatitis is characterized by fatty liver together with inflammatory cell infiltration into the liver and hepatocyte injury. Steatohepatitis is associated with inhibition of liver regeneration and triggers activation of liver fibrogenesis that leads to cirrhosis in 15-20% of patients (1). Patients with severe alcoholic hepatitis display a prolonged and intense inflammatory reaction and have a high risk of short-term mortality. Few advances have been made in the management of patients with alcoholic liver disease and there is an urgent need to identify novel therapeutic targets (1). Considerable progress has been made within the last decade towards better understanding of the molecular mechanisms underlying alcoholic liver disease progression, with the identification of complex interactions between non parenchymal cells, immune cells and hepatocytes (2). MOLECULAR MECHANISMS OF ALCOHOL-INDUCED STEATOSIS Steatosis results from several alterations of lipid metabolism driven by alcohol, i.e: i) increased lipolysis of peripheral fat stored in adipose tissue, that flows to the liver as nonesterified fatty acids; ii) combination of altered metabolic pathways within hepatocytes, including enhanced de novo synthesis of fatty acids within the liver (lipogenesis) and reduced fatty acid mitochondrial β-oxidation; iii) reduced hepatic fat export (3) (Figure 1). Alcohol-induced decrease in fatty acid oxidation. Alcohol is metabolized to acetaldehyde in hepatocytes by alcohol dehydrogenase (ADH) and cytochrome P4502E1, and acetaldehyde accounts for most of the toxic effects of alcohol. Acetaldehyde is subsequently converted to acetate by mitochondrial aldehyde BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 39 dehydrogenase (ALDH). Both ALD and ALDH use NAD+ as cofactor, producing an excess of reducing equivalent NADH. The resulting decrease in the NAD+/NADH ratio leads to reduction of mitochondrial fatty acid oxidation (3). Acetaldehyde also decreases fatty acid oxidation via inhibition of PPARα, a nuclear receptor that control the transcription of genes involved in fatty acid transport and oxidation. In addition, decrease in PPARα reduces fat export by counteracting alcohol-induced decrease in microsomal triglyceride transfer protein, a protein required for the assembly of VLDL prior to export (3). Another mechanism by which acetaldehyde decreases fatty acid oxidation is via inhibition of AMP protein kinase, an enzyme that enhances fatty acid oxidation by phosphorylating/inactivating acetyl CoA carboxylase, leading to inhibition of carnitine palmitoyltransferase 1, a rate limiting enzyme for fatty acid oxidation. Interestingly, AMP protein kinase is also a negative regulator of fatty acid synthesis, because Acetyl CoA carboxylase is a rate limiting enzyme for fatty acid synthesis (also see below) (3). Alcohol-induced fatty acid synthesis. Acetaldehyde increases lipogenesis via transcriptional/posttranscriptional regulation of sterol regulatory element binding protein 1-c (SREBP-1c), a transcription factor that regulate the expression key lipogenic enzymes. SREBP-1c is directly induced by acetaldehyde, or indirectly via alcohol-induced endoplasmic reticulum stress and hyperhomocysteinemia. SREBP-1c is also negatively controlled by AMPK, so that inhibition of AMPK by alcohol also contributes to enhanced lipogenesis (3). Alcohol-induced down regulation of factors that limit fat accumulation. In addition to inhibiting PPAR alpha and AMPK, alcohol also down regulates activators of AMPK, such as the adipokine adiponectin and the NAD+-dependent deacetylase sirtuin1. MOLECULAR MECHANISMS OF ALCOHOL-INDUCED STEATOHEPATITIS Clinical evidence point out the role of endotoxin, toll-like receptors, cytokines and chemokines and oxidative stress in the pathogenesis of alcoholic fatty liver disease; molecular mechanisms have mainly been delineated in experimental studies with rodents. The innate immune system (Figure 2) Kupffer cells. Compelling evidence indicate that Kupffer cells play a key role in the initiation and progression of alcohol induced liver injury (4). Chronic alcohol exposure triggers gut dysbiosis and enhances gut permeability, thereby increasing the serum level of gut-derived endotoxin (LPS) that correlates with disease severity. LPS activates Kupffer cells following binding to Toll-like receptor 4 (TLR4). Alcohol also sensitizes Kupffer cells to LPS by increasing oxidative stress, and primes Kupffer cells to respond to LPS by upregulating a number of proinflammatory mediators, including cytokines (TNF, IL1) and chemokines (MCP-1, CXC chemokines, IL8), that contribute to various steps of alcoholic liver disease progression, i.e hepatocyte steatosis, inflammatory cell recruitement, hepatocyte injury and activation of fibrogenesis (Figure 2) (4, 5). In addition, acetate may enhance cytokine release from Kupffer cells, via a mechanism involving acetylation of histones (6). Finally, recent data also demonstrate that the complement system may also contribute to alcohol-induced Kupffer cell activation and release of TNF-alpha, independently of LPS activation of TLR4 (7) . Tumor necrosis factor-α (TNF-α) is considered as a major mediator of alcohol-induced liver injury, as shown in a number of clinical studies, and on the basis of experimental data demonstrating the substantial reduction of hepatic steatosis, liver inflammation and hepatocyte apoptosis in TNF-R1 deficient mice and in rodents treated with TNF-α antibodies. However, anti TNF-α therapy of patients with alcoholic hepatitis showed increased mortality, owing to a high rate of infectious events in these patients (1, 2, 4, 5). Alcohol may also impair the antiinflammatory response and resolution of inflammation. Indeed, activated Kupffer cells release antiinflammatory mediators with hepatoprotective properties, such as interleukin 10 40 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE (IL10). Defective secretion of IL10 by blood monocytes is associated with TNF-α overproduction in patients with severe alcoholic hepatitis, that is likely to worsen inflammation and promote ALD progression. Moreover, alcohol down regulates adiponectin and the AMPK/sirtuin1 pathway, which display potent antiinflammatory properties for Kupffer cells. T Helper lymphocyte 17 (Th17). Th17 lymphocytes are a recently described class of CD4+ lymphocytes that produce interleukin 17 (IL17) and interleukin 22 (IL22). Differenciation of naïve CD4+ lymphocytes into Th17 cells is promoted by IL6 and IL1, that are overproduced by Kupffer cells during ALD. Plasma levels of IL17 and the number of infiltrating IL17 secreting cells in the liver are increased in patients with ALD. IL17 promotes neutrophil recruitment by enhancing the production of chemoattractants (IL8 and GRO-α) by hepatic stellate cells (8). Neutrophil recruitment. Migration of neutrophils into the liver is a major inflammatory event in patients with alcoholic steatohepatitis. In addition to IL17, accumulation of neutrophils is promoted by Kupffer cellderived cytokines and chemokines that are markedly up-regulated in patients with ALD such as TNF, IL1 and CXC chemokines (1, 4, 5). Oxidative stress (Figure 3). Increased oxidative stress and reduced antioxidant defense mechanisms are key features of alcoholic steatohepatitis in humans, and play a key role in hepatocellular injury (9). Hepatocytes and Kupffer cells are major sources of reactive oxygen species in response to chronic alcohol exposure, produced by cytochrome P450 2E1, NADP(H)oxidase, and inducible nitric oxide synthase. Increase in oxidative stress causes mitochondrial damage and lipid peroxidation and decrease proteasome activity, resulting in increased hepatocellular apoptosis. Hepatocellular injury is further amplified by a decrease in antioxidant defense mechanisms, since alcohol depletes mitochondrial glutathione. Depletion of S-adenosyl methionine (SAM) by alcohol contributes to reduction of glutathion levels, because SAM is a precursor for glutathione, and increase in endoplasmic reticlum stress, both pathways contributing to hepatocellular injury. In addition, reactive oxygen species produced by Kupffer cells via NADPH oxidase and inducible nitric oxide synthase contribute to inflammatory mediator production, via enhanced ROSsensitive signaling pathways (NF-kB, MAPK, AP-1, Egr1) (Figure 2). Alcohol-induced autophagy. Autophagy is an intracellular degradation pathway by which lysosomes degrade proteins and lipids, remove misfolding protein and damaged organelles including mitochondria. Experimental findings obtained in a model of bindge drinking indicate that alcohol activates autophagy in hepatocytes, leading to reduction of hepatocyte apoptosis and reduction of fat accumulation (10). The relevance of this protective effect of autophagy in patients with alcoholic liver disease remains to be clarified. CONCLUSION Despite recent advances in the understanding of the molecular mechanisms governing alcoholic liver disease progression, the development of new therapies is clearly awaited. Novel pathways have been identified, owing to the use of animal models that only recapitulate the first steps of the disease, i.e fatty liver, Kupffer cell activation with mild hepatocellular injury. Therefore, there is an urgent need to develop new animal models with more severe forms of ALD, to further validate the relevance of pathways and identified targets in more advanced steps of the disease. Treatment of alcohol-induced liver disease should ideally reduce steatogenesis, oxidative stress, inflammation and fibrogenesis, while sparing liver regeneration. In this respect, novel potential therapeutic targets have been identified, that include i) molecules that will modify gut microbiota (probiotics), neutralize LPS or antagonize TLR4 (4); ii) compounds targeting CXC chemokines, IL17 or their receptors, because of their major role in inflammatory cell (neutrophil) infiltration (2, 4, 7); iii) sirtuin activators and iv) molecules targeting cannabinoid receptors, i.e CB2 agonists and CB1 antagonists, because of their expected antiinflammatory, antisteatogenic, hepatoprotective and antifibrogenic effects (11, 12). Further translational research is clearly awaited to evaluate the therapeutic relevance of these newly identified targets. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 41 REFERENCES Lucey, M.R., Mathurin, P., and Morgan, T.R. 2009. Alcoholic hepatitis. N Engl J Med 360:2758-2769. Gao, B., and Bataller, R. 2011. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141:1572-1585. Sozio, M., and Crabb, D.W. 2008. Alcohol and lipid metabolism. Am J Physiol Endocrinol Metab 295:E10-16. Gao, B., Seki, E., Brenner, D.A., Friedman, S., Cohen, J.I., Nagy, L., Szabo, G., and Zakhari, S. 2011. Innate immunity in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 300:G516-525. Voican, C.S., Perlemuter, G., and Naveau, S. Mechanisms of the inflammatory reaction implicated in alcoholic hepatitis: 2011 update. Clin Res Hepatol Gastroenterol 35:465-474. Kendrick, S.F., O’Boyle, G., Mann, J., Zeybel, M., Palmer, J., Jones, D.E., and Day, C.P. 2010. Acetate, the key modulator of inflammatory responses in acute alcoholic hepatitis. Hepatology 51:1988-1997. Cohen, J.I., Roychowdhury, S., McMullen, M.R., Stavitsky, A.B., and Nagy, L.E. Complement and alcoholic liver disease: role of C1q in the pathogenesis of ethanolinduced liver injury in mice. Gastroenterology 139:664-674, 674 e661. Lemmers, A., Moreno, C., Gustot, T., Marechal, R., Degre, D., Demetter, P., de Nadai, P., Geerts, A., Quertinmont, E., Vercruysse, V., et al. 2009. The interleukin-17 pathway is involved in human alcoholic liver disease. Hepatology 49:646-657. Arteel, G.E. 2003. Oxidants and antioxidants in alcohol-induced liver disease. Gastroenterology 124:778-790. Ding, W.X., Li, M., Chen, X., Ni, H.M., Lin, C.W., Gao, W., Lu, B., Stolz, D.B., Clemens, D.L., and Yin, X.M. Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. Gastroenterology 139:1740-1752. Mallat, A., Teixeira-Clerc, F., Deveaux, V., Manin, S., and Lotersztajn, S. The endocannabinoid system as a key mediator during liver diseases: new insights and therapeutic openings. Br J Pharmacol 163:1432-1440. Louvet, A., Teixeira-Clerc, F., Chobert, M.N., Deveaux, V., Pavoine, C., Zimmer, A., Pecker, F., Mallat, A., and Lotersztajn, S. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology -54:1217-1226. 42 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 43 Figure 1 MECHANISMS OF ALCOHOL-INDUCED LIVER FIBROSIS Fabio Marra Florence, Italy E-mail: [email protected] Figure 2 Figure 3 KEY POINTS • Alcoholic liver disease has a broad spectrum of clinical-histological pictures, and fibrosis occurs only in a proportion of patients with alcohol abuse unless the patient presents with overt signs of cirrhosis it is not easy to predict the presence of fibrosis based on clinical and laboratory findings. • The pathogenesis of fibrosis in ALD is regulated by mechanisms unique to these conditions and by others common to the development of fibrosis in other chronic liver diseases. • Direct effects of chronic alcohol abuse that promote fibrogenesis include generation of acetaldehyde, induction of oxidative stress, alterations of innate immunity and increased gut permeability. • The fibrogenic process in ALD is an example of extensive cross-talk among liver resident and infiltrating cells, with paracrine and autocrine effects leading to injury, apoptosis, inflammation. CLINICAL ASPECTS OF FIBROSIS IN ALCOHOLIC LIVER DISEASE (ALD) ALD ranges between simple steatosis, alcoholic steatohepatitis (ASH), progressive fibrosis, cirrhosis and hepatocellular carcinoma. Moreover, patients with underlying ALD may experience episodes of alcoholic hepatitis (AH) that are associated with high mortality rate in its severe forms. Patients with mild ALD are usually asymptomatic or show unspecific symptoms such as fatigue or mild abdominal pain. Because alcohol abuse can lead to severe organ damage in the brain, peripheral nervous system, skin, heart, kidney and pancreas, patients may develop a variety of liver-unrelated symptoms. Patients with advanced fibrosis and cirrhosis may show typical exploratory findings, yet physical examination can be normal in patients with early cirrhosis. Decompensated cirrhotic patients may show signs of jaundice, ascites, asterixis, and variceal bleeding. In alcoholic patients, Dupuytren’s contractures, parotid gland enlargement and peripheral neuropathy can also be noted. The presence of an AH, which is usually associated with impairment of liver function and clinical decompensation, can be suspected based on clinical and biochemical data, yet a definitive diagnosis needs histological confirmation. The diagnosis of the existence and degree of liver fibrosis in patients with alcohol abuse is based in both noninvasive and invasive methods. Patients with mild to moderate fibrosis show mild increase of aminotransferases, especially AST, and elevated GGT. Advanced fibrosis with portal hypertension leads to decreased platelet count and eventually liver failure develops with elevated bilirubin levels and decrease albumin serum levels and prothrombin time. The use of serum markers of fibrosis (Fibrotest, ELF panel) has been shown to estimate the presence and degree of liver fibrosis. Imaging techniques such as ultrasonography detect steatosis and advanced fibrosis, but they fail to distinguish between steatosis and ASH and are not reliable to diagnosis mild fibrosis. The measurement of liver stiffness by elastography is also useful to evaluate the degree of fibrosis, yet its results can be influenced by the amount of steatosis and inflammation. The indications of liver biopsy in patients with ALD are under debate. It is particularly indicated in patients with unclear diagnosis or in those with aggressive disease. In addition to confirming the diagnosis, liver biopsy is also useful for ruling out other unsuspected causes of liver disease, better characterizing the extent of the damage, providing prognosis, confirm active alcohol intake and guiding therapeutic decisionmaking. Another indication is the diagnosis of superimposed AH, since there are no reliable noninvasive 44 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE methods to diagnose this severe condition. The pattern of fibrosis is not homogeneous in all patients. It can be pericellular, perisinusoidal, and ‘chickenwire’. Eventually, bridging fibrosis develops and the subsequent formation of regenerative nodules defines cirrhosis. FACTORS INFLUENCING FIBROSIS PROGRESSION IN ALD Although a positive correlation between cumulative alcohol intake and degree of liver fibrosis has been reported, extensive individual variability exists. The main environmental factors influencing the progression of liver fibrosis in patients with alcohol abuse include obesity and cigarette consumption. The role of metabolic factors such as insulin resistance is unclear, yet recent reports suggest that it may favor fibrosis progression. Moreover, it is known that genetic factors influence the organ-specificity of alcohol-related harmful effects. Family studies, twin concordance studies, and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 45 fibrosis’. Although chronic liver diseases share most of the profibrogenic mechanisms, the pathogenesis of fibrosis in ALD and in other conditions this conditions may have certain specificities. For this reason, several studies have recently focused on identify specific pathways leading to fibrosis in different etiologies of chronic liver disease. PATHOGENETIC MECHANISMS OF FIBROSIS SPECIFIC FOR ALD As discussed earlier, the spectrum of ALD ranges from liver steatosis to steatohepatitis, fibrosis, cirrhosis and hepatocellular carcinoma. The pathogenesis of steatosis includes increased fatty acid and triglyceride synthesis and inhibited mitochondrial ß-oxidation of fatty acids and enhanced hepatic influx of free fatty acids from adipose tissue and of chylomicrones from the intestinal mucosa. Alcoholic fatty livers can develop inflammatory infiltrate (mainly composed by polymorphonuclear cells) and hepatocellular damage, a prerequisite to the progression to fibrosis and cirrhosis. Genes encoding for alcohol-metabolizing enzymes and proteins involved in liver toxicity such as antioxidants and pro-inflammatory cytokines have been the main subject of investigations in genetic studies. The main enzymes involved in alcohol metabolism in humans are alcohol dehydrogenase (ADH), aldehyde dehydrogenase (ALDH), and cytochrome P450IIE1 (CYP2E1). Genetic factors influencing the activity of these enzymes and the rate of alcohol metabolism have been extensively studied. Because of its fibrogenic potential, variations in the generation of acetaldehyde may explain individual differences after abusive alcohol consumption. Polymorphisms in genes encoding pro-inflammatory cytokines known to participate in the pathogenesis of ALD have also been examined, including TNF-α, NFκB, IL-1β and IL-1 receptor antagonist, IL-2, IL-6 and IL-10. Other studies have investigated the role of genetic variations of factors involved in LPS-induced intracellular pathways including CD14 and TLR4. Patients with genetic variations of superoxide dismutase and gluthatione-S-transferase, powerful antioxidants, are a risk factor for developing severe ALD. Finally, a recent study indicates that variations of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) strongly influence the development of advanced fibrosis among Caucasians. Despite the high number of studies assessing the role of gene variations in the susceptibility of ALD, a well-designed large study performing a genome wide association analysis is still lacking, and a genetic test capable of identifying patients the susceptibility to develop advanced ALD is lacking. Different pathogenic factors are implicating in the development of liver damage and fibrosis (Figure 2). In this respect, ALD represents a clear example of the importance of cell-cell interaction and cross-talk within the liver. In fact, hepatocytes, Kupffer cells, HSC, and inflammatory cells recreuited from the bloodstream all contribute to the pathogenesis of damage and the development of fibrosis. Factors at diagnosis that predict the progression of ALD to cirrhosis are not well known. The main determinant of disease progression is the amount of alcohol intake and sustained abstinence. Thus, recent data suggest that higher alcohol intake is associated with a poor short-term prognosis. In addition, most observational studies indicate that age, female gender and overweight are risk factors for cirrhosis. The existence of a florid steatohepatitis at baseline is a major determinant of progression to cirrhosis and it also favors the development of clinical complications. Cytokines and inflammation: Several studies have indicated that inflammatory pathways are activated in the liver during ALD, including NF-κB and tumor necrosis factor-α (TNFα). Kupffer cells, activated lymphocytes, and macrophages infiltrating the liver tissue are sources of TNFα. GENERAL MOLECULAR ASPECTS OF THE FIBROGENIC PROCESS Hepatic fibrosis is the excessive accumulation of fibrillar extracellular matrix (ECM) within the liver which occurs in the context of chronic liver diseases and is considered the result of the persistent activation of a ‘wound healing’ response. In the setting of a chronic damage, activation of this process, evolved to protect the tissue from damage, results in the formation of a fibrotic scar which eventually alters the cellular and functional balance of the organ. A key role in fibrogenesis is played by myofibroblasts, which produce extracellular matrix and in general coordinate the ‘wound healing’ response (Figure 1). Hepatic stellate cells (HSC) are classically considered to be a major source of hepatic myofibroblasts, but other cell types inside or outside the liver have been suggested to contribute to the expansion of the myofibroblast population observed during injury, including portal fibroblasts and possibly cells recruited from the bone marrow. The possibility that epithelial cells contribute to the myofibroblast pool via a process of epithelial-mesenchymal transition has also been recently hypothesized, but its overall contribution to the fibrogenic process is debated. It is believed that the involvement of different populations of fibrogenic cells is dependent on the etiology of liver damage and the resulting development of distinct spatial patterns of fibrosis. In alcoholic liver disease, fibrosis develops primarily in the pericentral areas, with a picture referred to as ‘pericellular Products of alcohol metabolism may directly damage hepatocytes. Acetaldehyde, the major methanol metabolic product, binds to proteins and DNA resulting in functional alterations and protein adducts, which activate the immune system by forming autoantigens. It also causes mitochondrial damage and impairs glutathione function, leading to oxidative stress and apoptosis. Acetaldehyde has been also shown to interfere with TGF-beta signaling via Smad3. In addition, reactive oxygen species (ROS) generation and the resulting lipid peroxidation play a major role in the pathogenesis of ASH and fibrosis. Main sources of ROS include CYP2E1-dependent MEOS, mitochondrial electron transport system of the respiratory chain, NADH-dependent cytochrome reductase and xanthine oxidase. Moreover, chronic alcohol intake markedly up-regulates CYP2E1, which metabolizes ethanol to acetaldehyde and parallels the generation of ROS and hydroxyl-ethyl radicals. More recently, a possible involvement of the chemokine system has been suggested by several experimental data in humans and in experimental models of ALD. In alcoholic hepatitis, hepatic expression of several chemokines has been found to be upregulated, and in particular expression of CXC components correlated with neutrophil infiltration and prognosis. These data identify a group of novel targets for novel therapeutic approaches to the most severe forms of alcoholic liver disease. Endotoxin and TLRs: Alcohol abuse results in changes in colonic microbiota and increased intestinal permeability, leading to endotoxemia. i.e. an increase in plasma lipopolysaccharide (LPS) levels, which is released in the circulation due to an increase in intestinal permeability. A pivotal aspect of this host-bacteria interaction is the recognition of TLR4 on Kupffer cells, that induce TNF-α production and contributes to liver injury. Recent studies have also shown that HSC also express several members of the toll-like receptor (TLR) subgroups, such as TLR4 and TLR9. TLR4 activation triggers multiple intracellular signaling pathways, including NF-κB, and induces the expression of several profibrogenic cytokines. The resulting inflammatory milieu in the alcoholic liver leads to PMN infiltration, ROS formation and hepatocellular damage, which drive fibrogenesis. Finally, impairment in the ubiquitin-proteasome pathway leads to hepatocellular injury and hepatic inclusions of aggregated cytokeratins (a.k.a. Mallory-Denk bodies). Following exposure to a hepatotoxic agent such as alcohol, hepatocytes activate several signaling pathways 46 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE in order to resolve or restrict the possible cellular damage. In patients with ALD, cellular stress is severe and persistent, leading to hepatic cellular death (lipo-apoptosis) and necrosis by induction of the c-Jun N-terminal Kinase (JNK) signaling pathway. This process of persistent ethanol-induced hepatic injury is not restricted to hepatocytes, as many studies suggest the existence of a relevant crosstalk with other hepatic cell types. Indeed, ethanol-induced oxidative stress is also present in activated Kupffer cells, which are responsible for the secretion of pro-inflammatory cytokines, linking alcohol abuse to inflammation. Hepatic stellate cells (HSC) are activated in a paracrine manner by acetaldehyde and ROS produced by the metabolism of ethanol in the surrounding hepatocytes and Kupffer cells. ROS-dependent activation of HSC, upon ethanol-induced hepatocyte damage, leads to deposition of collagen and other extracellular matrix components. As a consequence, perivenular and periportal fibrosis is established, eventually leading to bridging fibrosis and cirrhosis. These changes are typical features of alcoholic fibrosis and often coexist with the findings of ASH. Chronic ethanol abuse decreases NK cell activity. NK cells are thought to participate in the killing of HSC after their activation, thus providing a mechanism for the limitation of fibrosis. In contrast, NK T-cells are activated early in the response to ethanol feeding. With respect to fibrosis, activation of NKT has been reported to have pro- or antifibrogenic actions, and their role in ALD-associated fibrosis needs to be further elucidated. MECHANISMS OF FIBROGENESIS COMMON TO ASH AND OTHER LIVER DISEASES, INCLUDING NASH Alcoholic and nonalcoholic steatohepatitis (NASH) have similar histological features and spectrum of disease. Therefore, it is not surprising that recent research has identified mechanisms that are in common between these two conditions. In addition, some fibrogenic mechanisms are operating also in the progression of other forms of chronic liver diseases. Apoptosis. ASH and other forms of liver injury are characterized by hepatocyte apoptosis, and generation of apoptotic bodies has been recognized as a potent profibrogenic stimulus. Endogenous cannabinoid system. Cannabinoids are a group of molecules with modulatory properties on liver fibrogenesis. HSCs express both cannabinoid receptors and inactivation of CB1 receptors decreases fibrogenesis by lowering hepatic TGF-β1 and reducing the accumulation of fibrogenic cells in the liver. The role of cannabinoids derived by HSC has also been implicated in the pathogenesis of alcohol induced steatosis. While rimonabant, the first CB1 antagonist to enter clinical practice, has been recently withdrawn from the market due to psychiatric side effects, a new generation of antagonists that do not cross the bloodbrain barrier are promising for the treatement of fibrogenic disorders. On the other hand, CB2 activation provides antifibrogenic signals. Imbalanced adipokine expression: Recent studies have highlighted a relation between adipokines and several aspects of ALD, including fibrosis. Data have been obtained particularly for leptin and adiponectin. Leptin has been shown to mediate profibrogenic effects on the liver. Hepatic stellate cells express functional leptin receptors and are directly responsive to leptin with a number of biological actions that collectively promote fibrogenesis. Besides an action on HSC, leptin also targets Kupffer cells and sinusoidal endothelial cells stimulating TGF-β expression. Adiponectin increases insulin sensitivity and provides anti-inflammatory signals. A direct antifibrogenic action of adiponectin has been demonstrated in animals undergoing toxic liver damage and adiponectin ameliorates liver damage in different models of steatohepatitis. Some of the anti-fibrogenic effects of adiponectin are dependent on activation of AMP-activated protein kinase, that is activated in hepatic stellate cells upon interaction of adiponectin with its cognate ligands. Along these lines, adiponectin has been shown to reduce hepatic damage and fibrogenesis in models of alcoholic liver disease, providing a molecular counterpart for the observed detrimental effect of obesity on the course of ALD. THE INTERNATIONAL LIVER CONGRESSTM 2012 47 CONCLUSIONS AND PERSPECTIVES Fibrosis in ALD has peculiarities that differentiate it from the one that is observed in other forms of liver disease, both from the pathological point of view and for the molecular mechanisms that characterize it. Nonetheless, some mechanisms are in common, particularly with nonalcoholic steatohepatitis but also with other forms of fibrogenesis. Application of translational research, which combines studies in humans with mechanistic information from preclinical investigation is the challenge for the discovery of new therapeutic targets in the near future. REFERENCES Bataller R, Rombouts K, Altamirano J, Marra F. Fibrosis in alcoholic and nonalcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2011; 25:231-44 Cohen JI, Nagy LE. Pathogenesis of alcoholic liver disease: interactions between parenchymal and non-parenchymal cells. J Dig Dis 2011;12:3-9. Cubero FJ, Urtasun R, Nieto N. Alcohol and liver fibrosis. Semin Liver Dis 2009;29:211-21. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1572-85 Gao B, Seki E, Brenner DA, Friedman S, Cohen JI, Nagy L, Szabo G, Zakhari S. Innate immunity in alcoholic liver disease. Am J Physiol Gastrointest Liver Physiol 2011;300: G516-25 Mencin A, Kluwe J, Schwabe RF. Toll-like receptors as targets in chronic liver diseases. Gut 2009;58:704-20. Marra F, Bertolani C. Adipokines in liver diseases. Hepatology 2009;50:957-69. Stickel F, Seitz HK. Alcoholic steatohepatitis. Best Pract Res Clin Gastroenterol 2010;24:683-93. Szabo G, Bala S. Alcoholic liver disease and the gut-liver axis. World J Gastroenterol 2010;16:1321Tam J, Liu J, Mukhopadhyay B, Cinar R, Godlewski G, Kunos G. Endocannabinoids in liver disease. Hepatology 2011;53:346-55 Figure 1 Basic features of activated stellate cells. Activation of stellate cells to myofibroblasts is associated with acquisition of phenotypic changes that make them more suitable to coordinate the wound healing response and fibrogenesis. Mediators implicated are indicated on the right. 48 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE THE INTERNATIONAL LIVER CONGRESSTM 2012 49 NOTES Figure 2 Overview of the pathogenetic pathways leading to fibrosis in alcoholic liver disease. The top part of the figure summarizes the mechanisms that are more specific to the pathogenesis of alcoholic fibrosis. The contribution of other pathways, such as obesity and the cannabinoid system, operating also in other chronic liver diseases is indicated in the bottom part. CLINICAL CASE : A PATIENT WITH CHRONIC ALD Alexandre Louvet, Florent Artru, Philippe Mathurin Lille, France E-mail: [email protected] KEY POINTS • Despite the fact that liver biopsy is still the gold standard for the diagnosis of alcoholic liver disease, serum biomarkers and transient elastography are relevant to establish liver fibrosis. • Tobacco consumption has a moderate negative impact on fibrosis progression in ALD, in contrary to coffee consumption. Overweight and drinking outside the meals also accelerate fibrosis progression. Few clinical data are available regarding binge drinking but it may be speculated that this pattern of consumption worsens the evolution of liver fibrosis. • Raised GGT and MCV are not good predictors of persistent alcohol consumption, especially in cirrhotic patients. • Disulfiram, naltrexone, acamprosate and baclofen are efficient in the prevention of alcohol relapse but only baclofen has been tested in cirrhotic patients. INTRODUCTION A 56-year old man is referred for abnormal liver tests. He has no past medical history. He is married and lives with his wife and his two children. He is not working but is a former employee in a bank. He recognizes a daily alcohol consumption of around 50-70 g/day (beer and spirits) that he mentions to have stopped 1 month ago. He stopped his alcohol consumption after his family doctor raises the possibility of alcoholic cirrhosis. He does not report any sobriety period before. He began to drink alcohol beverages at the age of 18 and was binge drinking during 10 years (from the age of 20 to 30), mainly with friends and colleagues but almost never during the meals. He does not report any hidden alcohol consumption and was never drinking alone. His motivation for long-term abstinence seems good, although he mentions to have still some craving episodes. He has no current symptoms and feels to be in good condition. Clinical examination does not reveal any spider naevi, swollen legs, hepatomegaly or jaundice. Body mass index is 31 kg/m2 and he reports to have become overweight at the age of 35. He does not report any marijuana or other drug consumption but has smoked a lot, from the age of 20 to 50 years (between 20 and 30 cigarettes a day). His biological tests are as follows: White cell count 9,200/mm3, hemoglobin 14.5 g/dL, MCV (mean corpuscular volume) 101 fl, platelet count 135,000/mm3, INR 1.12, serum creatinine 0.8 mg/dL, AST (aspartate aminotransferase) 89 IU/L (upper limit of normal value: 40 IU/L), ALT (alanine aminotransferase) 56 (upper limit of normal value: 40 IU/L), gammaglutamyltransferase 185 IU/L (upper limit of normal value: 55 IU/L), alkaline phosphatase 157 IU/L (upper limit of normal value: 240 IU/L), serum bilirubin 0.9 mg/dL, serum albumin 3.4 g/dL. Alpha-fetoprotein, ferritin and serum iron are within the normal ranges and screening is negative for HIV, HCV and HBV. Ultrasonography has already been performed and has shown liver brightness related to probable steatosis, however the examination was hampered by abdominal obesity. Question 1: If the General Practitioner is correct, give the patient characteristics that are present in this observation that may have led to the development of cirrhosis. Answer: Despite differences related to gender (females are more prone than males to develop hepatic damages at the same daily alcohol intake), a recent meta-analysis has shown that individuals drinking more than 25 g/ day are at higher risk of morbidity related to cirrhosis than the others (1), even if the risk of cirrhosis was far higher in patients drinking more than 120 g/day. Between these two cut-offs, many individuals develop 50 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 51 NOTES liver cirrhosis whereas others do not, even after several decades of exposure to ethanol, suggesting the major impact of cofactors for fibrosis progression. Overweight and obesity are well-documented risk factors development of cirrhosis (2). Alcoholic and non-alcoholic fatty liver disease share similar pathways for the of hepatocyte injury (e.g. activation of type 1 liver macrophages, resistance to adiponectin) and obesity is associated with a more rapid progression of hepatic fibrosis in experimental models (3). As example, in a series of more than 1,600 patients with an alcohol intake greater than 50g/day, liver biopsy found liver cirrhosis in 60% of overweight patients, as compared to 35% in non overweight (2). The risk of alcoholic liver disease is higher when alcohol is consumed outside mealtimes, leading to a risk of hepatic injury, cirrhosis and hepatocellular carcinoma (4). This is probably related to a more rapid absorption of ethanol and to changes in gut permeability, as may be observed in binge drinking. The deleterious impact of drinking outside mealtimes also seems to be related to changes in gastric alcohol dehydrogenase and hepatic glutathione (4). Regarding binge drinking, its definition is not consensual but the National Institute on Alcohol Abuse and Alcoholism has proposed the threshold of 5 drinks in the space of 2 hours (4 drinks for women). To date, we have no robust data that prove the negative impact of binge drinking on fibrosis progression (5). However, some experimental studies have suggested that binge drinking is associated with increased gut permeability that leads to the release of endotoxin and cytokines, therefore enhancing liver inflammation and fibrosis. Another key effect of binge drinking on the liver is mitochondrial dysfunction, caused either by lipid peroxidation and selective depletion of mitochondrial (5). Several studies indicate that cigarette smoking worsens fibrosis in liver diseases, especially in hepatitis C, hepatitis B and primary biliary cirrhosis (6). It must be acknowledged that no data are available in the specific setting of alcoholic liver disease. Tobacco is also a well-documented risk factor of HCC with risk-ratio ranging from 1.49 to 9.6, regardless of the cause (6). Thus, more attention must be paid to obtain tobacco withdrawal in patients suffering from chronic liver diseases, especially in alcoholic liver disease when considering the synergic risk of tobacco on oral, pharyngeal and esophageal cancers in heavy drinkers. In this patient, episodes of binge drinking, alcohol consumption outside meals, cigarette smoking and obesity may have promoted the evolution of fibrosis to cirrhosis. Question 2: What is your feeling about sobriety when considering the results of GGT, MCV and AST? Answer: Elevation in γ-glutamyltransferase (GGT) and mean corpuscular volume (MCV) are currently considered as indicators for chronic alcohol abuse, but no single laboratory marker can be considered as diagnostic in this setting (7). The sensitivity and specificity of GGT for chronic alcohol consumption above 50 g/day are 73% and 75% respectively, and it is important to point out that the specificity of γ-glutamyltransferase is far lower in patients with advanced fibrosis. However, the rate of GGT is usually higher in patients with alcoholic liver cirrhosis, as compared with patients with other liver diseases. Lastly, elevated GGT is frequently observed in obese patients, especially in men (8). Elevation in mean corpuscular volume is related to a direct toxicity of ethanol on the erythrocyte membrane. The diagnostic accuracy of an elevated MCV is not very different from that of GGT, with respective sensitivity and specificity at 52% and 85% (7). However, the relatively good specificity must be tempered by the possibility of other causes for macrocytosis in cirrhotics, in particular low folate concentration in serum (due to a certain degree of malnutrition) and/or acquired injuries of the erythrocyte membrane (such as spur cells or burr cells), which may cause hemolysis and disturbed MCV. Elevation in transaminases, especially aspartate amino transferase (AST) is commonly seen in alcoholic liver disease and its sensitivity is around 50% with specificity at 80%. The AST/ALT ratio is usually greater than 1 but this is commonly seen in patients with advanced liver disease, especially cirrhosis, regardless of the cause (9). In this patient, measurement of carbohydrate deficient transferrin (CDT) can be proposed but its good specificity (92%) is hampered by a sensitivity that is not better than that of GGT (69%). Thus, this parameter is mainly interesting when elevated. Question 3: You recommend liver biopsy to establish the diagnosis of cirrhosis but the patient refuses to undergo the procedure. Which alternative tools can be used to assess liver fibrosis? Answer: Liver biopsy is still the gold standard for the diagnosis of alcoholic liver disease. However, when considering the morbidity of this invasive procedure and the number of patients with abnormal liver tests related to chronic alcohol consumption, it is unrealistic to propose liver biopsy to all patients. It seems reasonable to screen heavy drinkers for fibrosis using non-invasive tools. Fibrotest®, FibrometerA® and Hepascore® are the three combinations of biomarkers that have proven their relevance in compensated alcoholic liver disease (10). The diagnostic accuracy of these three markers was comparable in terms of fibrosis extent in a recent prospective study of more than 200 patients who had undergone liver biopsy (10). The respective areas under the ROC curve were 0.83 for the three scores for the diagnosis of fibrosis greater or equal than F2 and were the following for the diagnosis of cirrhosis: 0.94 (Fibrotest®), 0.94 (FibrometerA®) and 0.92 (Hepascore®). These performances were superior to that of APRI, Forns and FIB4 scores but were not improved by their combination of one to another. Transient elastography (Fibroscan®) has also demonstrated to be a valid and reproducible non-invasive tool for the assessment of fibrosis in alcoholic liver disease. However, it must be kept in mind that it is not only influenced by fibrosis, but also by inflammation, cholestasis and abstinence or alcohol relapse. Nevertheless, two large studies have shown good AUROC curves: 0.92 (11) and 0.87 (12) for the diagnosis of cirrhosis. However, cut-offs for the definition of cirrhosis are far higher than those used for hepatitis C and the optimal value which predicts a METAVIR score F4 is still to be determined (19.5 kPa in (11) and 22.6 in (12)). In this patient, it seems reasonable to evaluate liver fibrosis using Fibrotest®, FibrometerA® or Hepascore® and to take measurements of liver stiffness using Fibroscan®. Question 4: Which pharmacological strategy do you recommend for sobriety maintenance? Answer: Persistence of craving episodes in this patient argues for a pharmacological support to reach long-term abstinence. Disulfiram inhibits the liver enzyme aldehyde dehydrogenase, leading to the accumulation of acetaldehyde and to a flushing reaction characterized by tachycardia, nausea, vomiting, and hypotension. Despite some heterogeneity between studies, a meta-analysis on more than 1,500 patients has shown that disulfiram used in a supervised manner was more efficient than placebo to reach abstinence Disulfiram has not been evaluated in patients with liver cirrhosis and systemic effects related to the pharmacological effect of disulfiram must lead to be very cautious in its use in these patients. A systematic review published in 2010 (13) has compelled 24 randomized controlled trials and has demonstrated that acamprosate, a glutamate antagonist, is effective in promoting abstinence in increasing abstinence duration by 11% as compared to placebo. Acamprosate was not associated with any hepatotoxicity but none of the studies included in this meta-analysis had included patients with liver cirrhosis. Naltrexone is an opioid antagonist that has been proved to maintain abstinence in several studies, especially when its long-acting injectable form is used (14). In the most recent series on more than 600 patients (14), the 380 mg monthly dose of naltrexone was more likely to maintain abstinence than the 190 mg dose or than the placebo (the 380 mg dose reducing heavy drinking by 25% as compared to placebo). There was no evidence for hepatotoxicity in this series but patients with transaminases greater than 3 times the upper limit of the normal value were excluded from the study. Lastly, naltrexone in combination with behavioural intervention seems to be more efficient than acamprosate in a large study in patients without alcoholic liver disease (15). Thus, naltrexone and acamprosate are promising drugs but they have not been tested in cirrhotic patients with alcoholic liver disease and are potentially responsible for hepatotoxicity in these patients, as well as 52 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE THE INTERNATIONAL LIVER CONGRESSTM 2012 53 NOTES disulfiram. The most promising drug for the maintenance of abstinence in alcoholic cirrhotic patients is baclofen. Baclofen is an agonist of the GABAB receptor which has demonstrated to be more effective than placebo in promoting alcohol abstinence in a study on 84 cirrhotic patients treated with baclofen or placebo for 12 weeks (16). Mean cumulative abstinence duration was 62.8 days in baclofen-treated patients as compared to 30.8 days in the placebo group. The safety profile of baclofen was good and no case of hepatotoxicity has been reported. Moreover, it is important to underline that patients with decompensated cirrhosis were included (38 and 43% of patients were Child-Pugh C in each group respectively). Another key-point of the management of alcohol dependence is brief interventions that must incorporate the features defined in the five As’ model: Ask about use, Advice to quit or reduce, Assess willingness, Assist to quit or reduce and Arrange follow up. These brief interventions have shown to reduce the amount of alcohol of than 50 g per week in men in a recent meta-analysis (17). more In this patient, alcohol dependence must be evaluated using the AUDIT score and brief interventions are to be encouraged. If a pharmacological support is needed, baclofen is the drug of choice, when considering the probable underlying cirrhosis. REFERENCES Rehm J, Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, Roerecke M. Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis. Drug Alcohol Rev 2010;29:437-445. Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease. Hepatology 1997;25:108-111. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1572-1585. Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, Saveria Croce L, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut 1997;41:845-850. Mathurin P, Deltenre P. Effect of binge drinking on the liver: an alarming public health issue? Gut 2009;58:613-617. Altamirano J, Bataller R. Cigarette smoking and chronic liver diseases. Gut 2010;59:1159-1162. Bell H, Tallaksen CM, Try K, Haug E. Carbohydrate-deficient transferrin and other markers of high alcohol consumption: a study of 502 patients admitted consecutively to a medical department. Alcohol Clin Exp Res 1994;18:1103-1108. Puukka K, Hietala J, Koivisto H, Anttila P, Bloigu R, Niemela O. Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase activity. Am J Clin Nutr 2006;83:13511354; quiz 1448-1359. Nyblom H, Berggren U, Balldin J, Olsson R. High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol Alcohol 2004;39:336-339. Naveau S, Gaude G, Asnacios A, Agostini H, Abella A, Barri-Ova N, Dauvois B, et al. Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease. Hepatology 2009;49:97-105. Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly JP, Brevet M, et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther 2008;28:1188-1198. Nahon P, Kettaneh A, Tengher-Barna I, Ziol M, de Ledinghen V, Douvin C, Marcellin P, et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. J Hepatol 2008;49:1062-1068. Rosner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev 2010:CD004332. Garbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, Loewy JW, et al. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. Jama 2005;293:1617-1625. Anton RF, O’Malley SS, Ciraulo DA, Cisler RA, Couper D, Donovan DM, Gastfriend DR, et al. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. Jama 2006;295:2003-2017. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 2007;370:1915-1922. Kaner EF, Dickinson HO, Beyer F, Pienaar E, Schlesinger C, Campbell F, Saunders JB, et al. The effectiveness of brief alcohol interventions in primary care settings: a systematic review. Drug Alcohol Rev 2009;28:301-323. 54 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE HISTOPATHOLOGICAL ASSESMENT OF ALCOHOLIC LIVER DISEASE Tania Roskams Leuven, Belgium E-mail: [email protected] KEY POINTS • Know the typical features of alcoholic liver disease (ALD) and the differences with other common etiologies of liver disease. • Understand the histopathological features which are most important in the prognostic assessment of ALD, in particular to make the differential diagnosis of so-called acute-onchronic liver disease and chronic decompensated liver disease. INTRODUCTION In the setting of alcoholic steatohepatitis (ASH), the clinician takes a liver biopsy to know 1) the etiology of the disease 2) eventual additional factors, 3) the stage of the disease, 4) the activity of the disease, 5) in case of sudden deterioration in the end stage the clinician wants to know if this is decompensation of end-stage cirrhosis or so-called acute-on-chronic liver disease. These different aspects will be discussed during this talk. When receiving a needle biopsy of the liver the first feature a pathologist assesses is the architecture. A special fibrous tissue stain is necessary: e.g. sirius red or Masson’s trichrome. In alcoholic or non-alcoholic steatohepatitis, a fine threadery perisinusoidal, pericellular type of fibrosis is seen, resulting in the typical chicken wire fibrosis. This type of fibrosis is caused by direct activation of stellate cells, which are located in the immediate vicinity of hepatocytes. Since alcohol is metabolized in the centrolobular area, the fibrosis starts in this area, followed by periportal fine threadery fibrosis. Centrolobular fibrosis can affect the draining centrolobular veins and cause outflow block at microscopical level. Paraportal shunt vessels and dilated sinusoids are signs of portal hypertension. The fine threadery perisinusoidal and pericellular type of fibrosis differs from biliary fibrosis, which is the result of ductular reaction associated with activation of periductular fibroblasts resulting in porto-portal septa. The fine threadery fibrosis in NASH also differs from the type of fibrosis in viral or auto-immune hepatitis which is the results of interface hepatitis or confluent necrosis following the blood stream from which inflammatory cells diapede: from portal tracts to central veins: that’s why in hepatitis portal-central septa are seen, which is not the case in biliary type of fibrosis. The next structures to be examined are the portal tracts. In ASH little inflammation is seen compared to viral or auto-immune hepatitis and the infiltrate which is present is mainly composed of polymorphonuclear leucocytes. Portal phlebosclerosis is commonly seen, especially in more advanced stages of the disease. At the interface with the parenchyma ductular reaction is often seen as a sign of regeneration, because alcohol inhibits the regenerative capacity of the hepatocytes, hence activating the progenitor cell compartment (Roskams et al 2003). It can also be the results of secondary sclerosing cholangitis which is also quite common in the more advanced stages of disease, either secondary to the liver fibrosis or secondary to sclerosing pancreatitis. Features are similar to primary sclerosing cholangitis: thickened basement membranes, ductular reaction and cholangiolitis, but ductopenia is lacking. A special histopathological features is ductular bilirubinostasis: ductules at the interface of the portal tracts with the surrounding parenchyma are dilated and contain bilirubin plugs. This is an early sign of infection before clinical signs are obvious. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 55 The parenchyma in (N)ASH shows steatosis: microvesicular, mediovesicular and finally macrovesicular. In alcoholic disease, the steatosis is localized in the centrolobular area since alcohol is metabolized there, while in (N)ASH steatosis is distributed more randomly and associated with glycogenated nuclei. Ballooning of hepatocytes and formation of Mallory-Denk bodies (MDB) are also typical for ASH. MDB surrounded by polymorphs are called satellitosis and are a sign of active alcohol use. To objectivate MDB an immunohistochemical stain for ubiquitin can be used. Also the presence of satellitosis is better objectivated using this stain. Megamitochondria are a sign of active metabolization of alcohol. Hepatocytic bilirubinostasis is a sign of decompensation of the hepatocyte function. Acute on chronic liver failure In the context of chronic liver insufficiency, the term “acute-on-chronic liver failure” (ACLF) was introduced about a decade ago in an attempt to demarcate a syndrome with a similar clinical context and onset, but with heterogeneity in etiology of underlying liver disease and rapidity of clinical presentation (Jalan 2002 and Laleman 2006). Although ACLF, in its first (only) working definition, was described as an acute deterioration in liver function in a patient with previously well-compensated liver disease due to the effects of a precipitating event, yet this entity remains poorly defined. Clinically, this syndrome is characterized by jaundice, hepatic encephalopathy, hemodynamic instability and/or hepatorenal syndrome, and leads to a mortality of 50 to 90% because of the combined impact of these manifestations The importance of this syndrome resides in the conceptual suggestion of reversibility or recompensation since if the patient can tide over the acute episode of liver failure and associated subsequent multi-organ dysfunction; he could re-emerge above the critical threshold of functional liver cell mass and as such preclude the need for transplantation (Jalan 2002, Sen 2002 and Laleman 2006). In this way, ACLF has to be distinguished from chronic relentless hepatic decompensation (CHD), which usually occurs in patients with end-stage cirrhosis as a result of progression of their underlying liver disease. Because this is deemed irreversible due to loss of regeneration potential, liver transplantation is the only therapeutic option. Accordingly the key elements in ACLF compared to the CHD state are the ability to recompensate (reversibility) and the presence of a precipitating hit, which initiates a cascade of devastating events. Whether this reversibility is related to regeneration potential has not been investigated yet. Therefore in a previous study (Katoonizadeh et al 2010) we aimed to address this question. In addition, we investigated the importance of early clinical characteristics, the identification and relative role of precipitating factors and a wide spectrum of histological parameters (Table). Upon histological proof of cirrhosis and use of the clinical working definition, we were able to characterize two different groups of patients in our homogenous population of patients with alcoholic cirrhosis. In an attempt to elucidate the different outcome despite relatively similar clinical presentation, we reviewed the two essential elements characterizing ACLF, namely regeneration potential and the influence of precipitating events. Regenerative ability was studied in the 2 groups by evaluating the degree of activation of HPCs and hepatocytes replication. Our results showed that HPCs were equally highly activated in both groups, while the number of proliferating hepatocytes was comparably low. Accordingly, difference in regenerative ability seems – at least histologically – not to explain the disparity in survival and challenges the quintessence of “regenerative potential” in the definition of ACLF. Although we admit to certain shortcomings related to the manner of assessment, at present histological assessment, however, remains by far the most ‘simple’, most clinically accessible and direct index of regenerative potential. If we next consider the effect of a potential precipitating event, we documented a key role for an apparently triggered and dysregulated inflammatory response. Our investigations revealed that in patients with ACLF features of infection such as SIRS and ductular bilirubinostasis at biopsy were early characteristics of ACLF. Increased susceptibility to infections in patients with (alcoholic) cirrhosis has already previously been reported and is now generally accepted (Wong 2005). In clinical practice, however, the problem is the lack of a highlysensitive, cheap, easily and rapidly available detection assays for detection of infection. In this setting, positive SIRS criteria, used and validated already earlier in septic shock and multi-organ failure (Muckart 1997), might represent an alternative approach and early additive tool. In our study, we clearly showed that 56 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE SIRS was an independent predictor of in-hospital mortality in ACLF. Another independent predictor of shortterm mortality was ductular bilirubinostasis on biopsy which is an important marker of sepsis and multiorgan failure (Lefkowitch 1982). Of high importance, ductular bilirubinostasis on histology showed a clear correlation with development of infection during hospitalization. Taken together the findings of this study suggest that SIRS and ductular bilirubinostasis, as early signs of infectious complications, might be helpful to detect ACLF in a stage of the disease when therapeutic interventions might still be effective. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 57 Table 2 A histopathological prognoctic scoring system is currently being validated internationally (Altamirano et al). Table 1 Multivariate analysis ascertained the following parameters to be related to mortality: age (P= 0.0003), SIRS within the first 48 hours of admission (P=0.05) and the histological presence of marked ductular bilirubinostasis (P=0.04) and Mallory bodies (P=0.01). In the CHD group, the small number of death did not allow us to establish significant differences for in hospital mortality in comparison with the ACLF group Results Individual parameters: Clinical parameters predictive of in-hospital mortality in ACLF within 48 hours of admission and histological features predictive for mortality at the moment of diagnosis are listed in table 4. Univariate analysis of a wide spectrum of clinical parameters showed age, INR and SIRS as predictors of in-hospital mortality. At the moment of diagnosis (around 1 week after admission) serum creatinine (P=0.008) and bilirubin (P=0.01) levels also predicted outcome. Among histological features marked ductular bilirubinostasis (P=0.003) (Figure 3) and Mallory bodies (P=0.002) predicted in-hospital mortality. 58 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE REFERENCES Lucey, M.R., Mathurin, P., and Morgan, T.R. 2009. Alcoholic hepatitis. N Engl J Med 360:2758-2769. Gao, B., and Bataller, R. 2011. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141:1572-1585. Sozio, M., and Crabb, D.W. 2008. Alcohol and lipid metabolism. Am J Physiol Endocrinol Metab 295:E10-16. Altamirano J, Miquel R, Katoonizadeh A, et al. Development and validation of a novel histological classification with prognostic value for alcoholic hepatitis. Hepatology 2011;54:968A. Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif 2002; 20:252-61 Laleman W, et al. Effect of the molecular adsorbent recirculating system and Prometheus devices on sytemic haemodynamics and vasoactive agents in patients with acut-on-chronic alcoholic liver failure Crit Care 2006; 10: R108 Lefkowitch JH: Bile ductular cholestasis: an ominous histopathologic sign related to sepsis and ‘cholangitis lenta’. Hum Pathol 1982; 13(1): 19-24 Roskams et al Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 2003; 1301-1311 Sens S, Williams R, Jalan R. The pathophysiological basis of acute-on-chronic liver failure. Liver 2002; 22. 5-13 Wong et al. Sepsis in cirrhosis: report of the 7th meeting of the International Ascites Club. Gut2005; 54;718-725 BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 59 NONINVASIVE TOOLS IN THE DIAGNOSIS OF ALD Sebastian Mueller Heidelberg, Germany E-mail: [email protected] KEY POINTS • ALD is underestimated due to limitations in noninvasively screening for the disease. • Measurement of liver stiffness (LS) by transient elastography is now the method of choice to screen for alcoholic liver fibrosis/cirrhosis (F3/4 stage). Alternative tools such as acoustic radiation force imaging (ARFI) or magnetic resonance elastography (MRE) are under investigation. • Normal liver stiffness (<6 kPa) excludes manifest fibrosis. • For optimal interpretation, transient elastography should be performed simultaneously with an abdominal ultrasound to exclude stiffness modifying conditions (congestion, cholestasis, morphological abnormalities). • In addition, correct interpretation of transient elastography requires actual laboratory tests (namely transaminases). Patients with LS<30 kPa and GOT>100 U/ml should be re-evaluated after alcohol detoxification to precisely determine the fibrosis stage in the absence of significant inflammation. • Future focus: identify rapid fibrosers, longterm follow up, prevalence of ALD in general population, alternatives for patients not measurable by transient elastography. INTRODUCTION Although being the most common liver disease, ALD is generally underreported, underdiagnosed and, therefore, underestimated in health statistics. This is mainly due to present limitations in the noninvasive diagnosis of the disease but will change with the recent introduction of liver stiffness measurements. Since no specific marker exists as compared to viral hepatitis, ALD is typically recognized only at late cirrhotic stages of decompensation. However, about 40% of patients with cirrhosis are asymptomatic and even routine laboratory tests are normal in 40%. Moreover, liver biopsy which is the present gold standard for liver cirrhosis, is a painful, costly and invasive technique that has an unacceptable high sample error of ca. 30% (Fig. 1). Especially this high sample error prevents the usage of histology to screen and follow up for advanced ALD. The diagnosis of ALD has to consider the different clinical stages including alcoholic fatty liver, steatohepatitis and cirrhosis. There is no single parameter that allows to establish the diagnosis of ALD. Its diagnosis is rather based on a combination of various parameters including history of alcohol abuse, clinical, laboratory and imaging findings, transient elastography or biopsy. Clinical presentation and physical examination in patients with ALD varies considerably and these signs are suggestive but not confirmatory with low sensitivity. In single cases, namely severe forms of steatohepatitis and suspected co-morbidities, liver histology is indicated to exclude other etiologies and determine the prognosis for potential therapeutic interventions. Recently, transient elastography has drastically improved the non-invasive assessment of fibrosis in patients with ALD. With and without optimized algorithms, its accuracy significantly exceeds serum fibrosis markers to identify and follow up fibrosis stages. It will also lead to first robust prevalence data of advanced ALD. Thus, in a study on more than 1000 apparently healthy people over 45 years, 7.5% had advanced fibrosis or cirrhosis with 36% having ALD [1]. 60 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Early non-invasive screening of people at high risk to progress to or with advanced ALD will also improve therapeutic options. First, non-addicted patients at high genetic risk for fibrosis progression due to PNPLA3 variant mutation can be identified at early stages. These patients can be easily motivated to completely abstain from alcohol being aware of their increased liver stiffness. Second, newly identified patients with asymptomatic cirrhosis can be screened for complications (varices, HCC) and earlier enrolled in transplant programs. Third, the role of alcohol consumption and its negative effect on other liver disease namely HCV or NAFLD can be identified and addressed earlier. GENERAL CLINICAL DIAGNOSIS OF ALD Most patients with moderate forms of ALD are asymptomatic and it can be only detected by appropriate sreening methods. Some patients can show signs suggestive of harmful alcohol drinking such as bilateral parotid gland hypertrophy, muscle wasting, malnutrition, Dupuytren’s sign and signs of symmetric peripheral neuropathy. In patients with cirrhosis, most physical findings are not specific of the etiology. However, some signs such gynecomastia and extensive spider angiomas may be more frequently seen in those with alcohol as the main cause of liver disease. The diagnosis of ALD is frequently suspected upon documentation of excess alcohol consumption > 30 g/d and the presence of clinical and/or biological abnormalities suggestive of liver injury. However, screening of ALD is difficult as significant proportions of patients with histological features of ALD do not show any clinical symptoms. Liver disease is shown by physical examination, laboratory, imaging or elastography findings. In contrast to the poorly sensitive physical examination, initial stages of ALD such as AFL or ASH can be diagnosed e.g. by ultrasound or laboratory tests. Routine blood tests such as MCV, GGT, AST and ALT can indicate early ALD, endstage ALD is suspected by decreased liver function tests and thrombocytopenia. While elevated transaminases are indicative of ongoing hepatocellular inflammation or destruction, GGT is not related to liver function per se and requires careful discrimination from cholestatic and biliary liver disease or others. DIAGNOSIS OF ALD BY BLOOD TESTS Routine blood tests such as mean corpuscular volume (MCV), GGT, AST and ALT can indicate early ALD whereas advanced ALD is suspected if there is decreased albumin, prolonged prothombin time, increased bilirubin level or thrombocytopenia. Although no single laboratory marker definitely establishes chronic alcohol consumption, carbohydrate deficient transferrin (CDT) and GGT are the most frequently used markers to detect previous alcohol consumption [2]. Indeed, the sensitivity for detection of daily ethanol consumption >50 g of CDT (69%) and GGT (73%) are higher than those of AST (50%), ALT (35%), and MCV (52%) [3]. The specificity of CDT was 92%, compared with 75%, 82%, 86%, and 85% for GGT, AST, ALT, and MCV, respectively [3]. As the measurement of GGT is easy and inexpensive, it remains the most frequently used marker for early detection of chronic alcohol misuse [4]. GGT is typically 4 times higher in ALD patients as compared to other liver diseases [5] and can reach up to 4000 U/ml in some individuals. However, GGT looses its alcohol specificity in more advanced stages. AST is typically elevated to a level of 2-6 times the upper limits of normal in severe alcoholic hepatitis while AST levels of more than 300 IU/L are rarely seen. In about 70% of patients, the AST/ALT ratio is higher than two, which is especially relevant for patients without cirrhosis [6]. Combination of these routine blood test further increases the accuracy to diagnose ALD. A sensitivity and specificity > 90% has been demonstrated for a combination of GGT, MCV, IgA, CDT, and AST/ALT ratio [7]. NON INVASIVE TESTS TO ESTIMATE LIVER FIBROSIS (FIG. 2). Hepatic Imaging techniques Imaging techniques such as ultrasonography, MRI and CT may allow the detection of fatty liver, help exclude other causes of chronic liver disease and contribute to the assessment of advanced liver disease and its complications independent of the etiology [8]. However, imaging studies do not have a role in establishing alcohol as the specific etiology of liver disease. The major role of imaging techniques is to exclude other causes of abnormal liver tests in a patient who abuses alcohol, such as obstructive cholestasis, or infiltrative and neoplastic diseases of the liver. With respect to fibrosis assessment, all imaging techniques have to rely BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 61 on so called definite morphological signs of cirrhosis such as nodular aspects of the liver or recanalization of the umbilical vein. Despite sometimes high diagnostic accuracy for the detection of alcoholic liver cirrhosis (ALC) under study conditions, imaging techniques are especially limited in the daily routine in diagnosing compensated liver cirrhosis (sensitivity <70%). Steatosis may be screened using ultrasonography, CT and MRI. Among those methods, ultrasound probably has the lowest sensitivity and specificity, especially when steatosis is below a threshold of 20-30%. Newer ultrasound based techniques such as CAP (controlled attenuation parameter) are more reproducible and quantitative with an AUROC up to 90% [9]. MRI and MR spectroscopy are reliable tools for assessing the amount of steatosis but the standardization of sequence characteristics are not established and their cost and avaibility are limiting [10, 11]. Sensitivity and specificity range from ca. 60-90%. In clinical practice, ultrasonography may be proposed in heavy drinkers as a screening procedure for steatosis [12] and should be certainly performed in all patients previous to transient elastography to avoid misinterpretations of increased liver stiffness [13]. Ultrasonography is also very useful in detecting signs of advanced stages of ALD such as portal-systemic collaterals and splenomegaly and to exclude other morphological abnormalities. Serum markers A large number of non-invasive bio-markers of fibrosis has been developed mostly for viral hepatitis [14] but also for ALD [15-17] (Fig. 2 and 3). So called direct tests integrate markers that directly reflect the deposition or removal of extracellular matrix such as hyaluronate, laminin, YKL-40, procollagen III N-petide (PIIIP), type IV collagen, collagenases, matrix metalloproteases and tissue inhibitory metalloprotease-1 (TIMP1). Other, so called indirect serum markers include routine blood tests such as prothrombin index, platelet count, AST/ALT ratio that are more or less related to liver function of advanced liver disease. These tests have been predominantly studied in patients with viral hepatitis, thus, different cut-offs may have to be considered when using such biomarkers for ALD. In first direct comparative studies in ALD patients, the diagnostic accuracy of transient elastography clearly exceeded those of serum markers although no optimized TE algorithms were used as will be discussed later [16] (Fig. 4). Despite reaching an AUROC of up to 0.95 in individual studies on ALD patients, the specific challenge of serum markers is that they are not organ specific and will also respond to remodeling and inflammation (Fig. 5). Although widely propagated in patients with viral hepatitic C, AST to platelet ratio index (APRI) is of limited usefulness in patients with ALD [16, 18]. Fibrotest® is a serum biomarker of fibrosis combining alpha-2macroglobulin, haptoglobin, GGT, ApoA1 and bilirubin, corrected for age and sex [19]. It seems to have high diagnostic potential for the detection of significant fibrosis in patients with ALD. In a study of 221 consecutive patients with biopsy-proven ALD, the mean Fibrotest® value ranged from 0.29 in those without fibrosis to 0.88 in those with cirrhosis and its AUROC for the diagnosis of cirrhosis was at 0.95 [20]. FibrometerA®, combining PT, alpha-2-macroglobulin, hyaluronic acid and age has similar diagnosic accuracy in ALD [21]. In the validating step, the Fibrometer® AUROC curve was 0.892 in overall patients and 0.962 in patients with ALD. Hepascore® combines bilirubin, GGT, hyaluronic acid, alpha-2-macroglobulin, age and gender. The combination of The diagnostic accuracies of Fibrotest®, Fibrometer® and Hepascore® were compared in patients with ALD [15]. The diagnostic values of FibrometerA® and Hepascore® did not differ from that of FibroTest® for advanced fibrosis (AUROCs around 0.80) and cirrhosis (AUROCs around 0.90), and were significantly greater than those of non-patented biomarkers (APRI, Forns, FIB4). The combination of any of these tests was useless in improving diagnostic performance [15]. In addition to their diagnostic performance in the screening of fibrosis, non invasive tests may be useful in predicting liver-related mortality as shown in a study of patients with ALD followed-up for more than 8 years, where survival was correlated with baseline noninvasive fibrosis score [15]. ELF®, a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum [17], may also predict clinical outcomes in patients with chronic liver disease on long term follow-up [22]. However, its utility has not been fully evaluated in large cohorts of alcoholic patients. Taken together, with the recent improvements on transient 62 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE elastography, serum markers seem to be limited in patients with ALD to those that are not accessible by TE. Transient elastography Assessment of liver stiffness (LS) by transient elastography (TE) has revolutionized the diagnosis of fibrosis/ cirrhosis in patients with ALD [13, 23, 24]. Although TE/Fibroscan was the first technique widely used alternative techniques such as ARFI or magnetic resonance elastography are currently under investigation and seem to be comparable with regard to accuracy (Fig. 6). Major advantage of TE is that the results are a) noninvasive b) immediate (results obtained within 10 min) c) can be performed in >90% of patients, and d) has a very small sample error of less than 5% [25] (Fig. 7). These characteristics render TE an ideal tool for diagnosis, screening and follow up of ALD patients. LS of 8 and 12.5 kPa represent generally accepted cut-off values for F3 and F4 fibrosis whereas LS values below 6 kPa are considered as normal and exclude ongoing liver disease (Fig. 8 and 9). LS highly correlates with portal pressure and esophageal varices and HCC are likely at values > 20 kPa [26, 27]. The major studies solely focusing on ALD patients demonstrated the usefulness of TE for fibrosis stage F3 and F4 with an AUROC>0.92 [16, 28-30]. However, especially in those studies that did not consider the degree of steatohepatitis, cut off values for F3 and F4 fibrosis were considerably higher as compared to patients with HCV infection (Fig. 10). Meanwhile, several conditions are known that increase LS irrespective of fibrosis stage which include: hepatic infiltration with tumor cells, all inflammatory conditions (hepatitis) [31, 32], deposition of amyloid [33], liver congestion [34], and mechanic cholestasis [35] (Fig. 11 and 12). Histological subanalysis confirmed that besides fibrosis stage conditions of increased pressure and typical features of ALD such as ballooning, Mallory-Denk body deposition and perisinusoidal inflammatory infiltrates highly correlate with LS but not steatosis [29] of the demonstrated thatThe knowledge of these conditions has led to more optimized diagnostic algorithms in using and interpreting TE in the clinical context [13]. This is especially required for ALD patients since these patients may present with a variety of clinical features (steatosis, steatohepatitis, cardiaque insufficiency, cholestasis, HCC) that all may interfere with TE. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 63 First preliminary studies indicate that 1. TE will also help us to discriminate between relapsers and abstainers, 2. TE may even directly affect drinking behaviour most likely in non-addicted patients not being aware of their individual fibrosis risk and 3. TE will allow us to screen the population for cirrhosis to obtain first robust prevalence data on alcoholic liver cirrhosis. Thus, a small study on 23 heavy drinkers admitted for alcohol detoxification over 7 days were followed up by TE over 60 days [36] (Fig. 16). Liver stiffness significantly decreased (-20%) in abstinent patients but increased (32%) in those who continued to drink. In another important study, liver stiffness was measured by TE in 1190 subjects >45 years old from a general population attending for a medical check-up were consecutively enrolled in the study [1] (Fig. 17). All subjects were submitted to medical examination and laboratory tests in addition to LSM, performed on the same day by a single operator. Subjects with LS values >8 kPa were referred to a liver unit for further investigations. 89 (7.5%) had LSM >8 kPa including nine patients with LSM >13 kPa. Despite the fact that normal liver tests were observed in 43% of them, a specific cause of chronic liver disease was found in all cases. ALD was the cause in 27 patients either alone or in combination with NAFLD. Liver biopsy could be obtained for 27 patients, including all nine patients with LS >13 kPa. Liver biopsy confirmed liver cirrhosis in these 9 patients with LS>13 kPA due to ALD (n=5), chronic hepatitis C (n=3) or chronic hepatitis B (n=1). The 18 remaining biopsies showed liver fibrosis in all cases except one (isolated steatosis), with ALD and NAFLD being present in six and eight cases, respectively. Importantly, three of the patients with confirmed cirrhosis due to ALD stopped drinking immediately until now. The study indicates that 1. TE is a useful and specific procedure to screen for cirrhosis in the general population, 2. advanced fibrosis and cirrhosis is much higher in the general population as assumed so far (up to 7%) and 3. a significant proportion of patients with alcoholic cirrhosis have normal lab tests but will stop drinking immediately upon diagnosis of advanced liver disease. Figure 1: Gommorrhi silberfärbung, sample error, several papers estimated 15-50% The major confounding condition in ALD patients that increases LS is steatohepatitis. This problem was addressed in a recent study on 101 biopsy proven patients with ALD [29]. Sequential LS analysis before and after normalization of serum transaminases was performed in a learning cohort of 50 patients with ALD admitted for alcohol detoxification (Fig. 13 and 14). LS decreased in almost all patients within a mean observation interval of 5.3 days. The decrease in LS correlated best with the decrease in AST. No significant changes in LS were observed below AST levels of 100 U/L. By excluding those patients with AST > 100 U/L at the time of LS assessment in a second validation cohort of 101 biopsy proven ALD patients, AUROC for the detection of F3 and F4 fibrosis could be both increased to 0.94. Meanwhile, these observations have been confirmed in two independent study populations. The actual diagnostic algorithm for TE to screen ALD patients is as follows (Fig. 15). If TE can be correctly performed (>70%) with the M probe advanced fibrosis can be robustly excluded in typically >40% of patients. Patients with increased LS>8 kPa should undergo simultaneous abdominal ultrasound and laboratory tests that should include AST levels. If morphological abnormalities, congestion or cholestasis can be excluded by ultrasound and AST levels are <100 U/l, TE can be interpreted directly according to above established cut-off values. If inflammation is present with AST levels > 100 U/l, patients should abstain from alcohol until transaminases have normalized and LS can be reassessed. Likewise, interventions can be applied to patients with congestion (diuretics) or mechanic cholestasis (biliary drainage). Only if LS>30 kPa, the diagnosis of liver cirrhosis can be established with certainty despite the presence of severe steatohepatitis. In cases of invalid measurements with the M probe, most patients can be successfully measured with the XL probe (>95%). The role of alternative tools to assess liver stiffness such as ARFI and MRE or serum markers in the remaining patients needs to be addressed in the future. In addition, the accuracy of liver biopsy in assessing fibrosis is limited due to sampling error and interobserver variability [2, 3, 4, 5, 6]. 2 Abdi W, Millan JC, Mezey E. Sampling variability on percutaneous liver biopsy. Arch Intern Med 64 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE No sampling variability was found for fatty liver, alcoholic hepatitis, nonspecific hepatitis, fulminant hepatitis, leukemic infiltrate, and venous congestion. Cirrhosis was diagnosed in 80% of cases at the first biopsy but in all cases after three biopsies. Chronic aggressive and chronic persistent hepatitis were diagnosed correctly in two of three cases each at the first biopsy, and in all cases after three biopsies. Metastatic carcinoma was detected in 46% of cases at the first biopsy and in 69% after three biopsies. Granulomas were missed once on the first biopsy, but found on a subsequent biopsy. The amounts of fat and fibrosis in the biopsy specimens often were not representative of the amounts present at autopsy. 3 Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38:1449-57. Surgical samples of livers from patients with chronic hepatitis C were studied. Measurement of fibrosis was performed on the whole section by using both image analysis and METAVIR score (reference value). From the digitized image of the whole section, virtual biopsy specimens of increasing length were produced. Fibrosis was assessed independently on each individual virtual biopsy specimen. Results were compared with the reference value according to the length of the biopsy specimen. By using image analysis, the coefficient of variation of fibrosis measurement with 15-mm long biopsy specimens was 55%; and for biopsy specimens of 25-mm length it was 45%. By using the METAVIR scoring system, 65% of biopsies 15 mm in length were categorized correctly according to the reference value. This increased to 75% for a 25-mm liver biopsy specimen without any substantial benefit for longer biopsy specimens. Sampling variability of fibrosis is a significant limitation in the assessment of fibrosis with liver biopsy. In conclusion, this study suggests that a length of at least 25 mm is necessary to evaluate fibrosis accurately with a semiquantitative score. Sampling variability becomes a major limitation when using more accurate methods such as automated image analysis 4Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000;32:477-81. 5Maharaj B, Maharaj RJ, Leary WP, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet 1986;1:523-5. In an investigation to determine the influence of sampling variability on the diagnostic yield of liver biopsy, 3 consecutive samples were obtained from each of 75 patients by redirecting the biopsy needle through a single entry site. In 14.7% of patients all 3 specimens were normal, and in 36% there were similar abnormalities in all 3 specimens. In the other patients, sampling variability between specimens was present. In those patients with cirrhosis, hepatocellular carcinoma, metastatic carcinoma, or hepatic granulomas the histological abnormality was present in all 3 biopsy specimens in only 50%, 54.5%, 50%, and 18.8% of patients, respectively. No complications were recorded. These findings show that important pathology can be overlooked if only a single biopsy specimen is taken, and that the method of obtaining 3 consecutive specimens improves the diagnostic yield of liver biopsy without an associated increase in complications. Regev A, Berho M, Jeffers LJ, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614-8. The aim of this study was to determine the rate and extent of sampling error in patients with chronic hepatitis C virus infection, and to assess the intraobserver variation with the commonly used scoring system proposed by Scheuer and modified by Batts and Ludwig. METHODS: A total of 124 patients with chronic hepatitis C virus infection underwent simultaneous laparoscopy-guided biopsies of the right and left hepatic lobes. Formalin-fixed paraffin-embedded sections were stained with hematoxylin and eosin and with trichrome. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 65 The slides were blindly coded and randomly divided among two hepatopathologists. Inflammation and fibrosis were scored according to the standard grading (inflammation) and staging (fibrosis) method based on the modified Scheuer system. Following the interpretation, the slides were uncoded to compare the results of the right and left lobes. Fifty of the samples were blindly resubmitted to each of the pathologists to determine the intraobserver variation. RESULTS: Thirty of 124 patients (24.2%) had a difference of at least one grade, and 41 of 124 patients (33.1%) had a difference of at least one stage between the right and left lobes. In 18 patients (14.5%), interpretation of cirrhosis was given in one lobe, whereas stage 3 fibrosis was given in the other. A difference of two stages or two grades was found in only three (2.4%) and two (1.6%) patients, respectively. Of the 50 samples that were examined twice, the grading by each pathologist on the second examination differed from the first examination in 0% and 4%, and the staging differed in 6% and 10%, respectively. All observed variations were of one grade or one stage. CONCLUSIONS: Liver biopsy samples taken from the right and left hepatic lobes differed in histological grading and staging in a large proportion of chronic hepatitis C virus patients; however, differences of more than one stage or grade were uncommon. A sampling error may have led to underdiagnosis of cirrhosis in 14.5% of the patients. These differences could not be attributed to intraobserver variation, which appeared to be low. In addition, the accuracy of liver biopsy in assessing fibrosis is limited due to sampling error and interobserver variability [2, 3, 4, 5, 6]. Figure 2 66 POSTGRADUATE COURSE SYLLABUS Figure 3 ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 67 The Fibrotest® (Biopredictive, Paris, France) score was determined using the following equation:22 4.467 log [A2M (g/L)] - 1.357 log [haptoglobin (g/L)] + 1.017 log [GGT (IU/L)] + 0.0281 x [age (years)] + 1.737 x log [bilirubin (μmol/L] - 1.184 x [Apo-A1 (g/L)] + 0.301 x gender (female = 0, male = 1) - 5.540. The Fibrometer® (BioLiveScale, Angers, France) score was calculated as follows:6 -0.169 PT (%) + 0.015 A2M (mg/dL) + 0.032 HA (μg/L) - 0.140 age (years) + 16.541. The PGA & -PGAA indices were calculated by adding the 4 laboratory parameters (PT, GGT, Apo-A1 and A2M) scored on a 0-4 scale according to published methods.3,13 The APRI was calculated as described elsewhere.16 Blood hyualuronic acid levels were measured with a immunoenzymatic assay. Lastly, the Hepascore logistic regression model was calculated using the following equation:18 y = exp [-4.185818 - (0.0249 x age) + (0.7464 x gender) + (1.0039) x A2M) + (0.0302 x HA) + (0.0691 x bilirubin) (0.012 x GGT)]. The Hepascore is defined as y/1+y. Figure 4 Figure 5 Figure 6 68 POSTGRADUATE COURSE SYLLABUS Figure 7 Figure 8 ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 69 Figure 9 Already first study included ALD 50 studies all liver diseases F3/F4, cut of values 2 von 3 im FS unterschaetzten Pat. scheinen Leberzirrhose zu haben 10 Pat. sind von Histologie unterschaetzt worden, bei 4 keine ausreichenden Informationen, bei den restlichen 6 in jedem Fall Zeichen der Leber zirrhose Conclusion: FS entdeckt nichtinvasiv 3x mehr Zirrhosen, sample error Figure 10 70 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, Darriet M, Couzigou P, De Ledinghen V. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005 Feb; 128(2): 343-350 Marcellin P, Ziol M, Bedossa P, Douvin C, Poupon R, de Ledinghen V, Beaugrand M. Non-invasive assessment of liver fibrosis by stiffness measurement in patients with chronic hepatitis B. Liver Int 2009 Feb; 29(2): 242-247. BARCELONA . SPAIN APRIL 18 - 19/2012 Figure 12 Higher ctu off in ALD, cite studied, By the wa also PBC and PSC higher cut offs, in heart failure not measurable Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly JP, Brevet M, Grignon P, Lion S, Le Page L, Dupas JL. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther 2008 Nov 15; 28(10): 1188-1198. 39. Kim SG, Kim YS, Jung SW, Kim HK, Jang JY, Moon JH, Kim HS, Lee JS, Lee MS, Shim CS, Kim BS. [The usefulness of transient elastography to diagnose cirrhosis in patients with alcoholic liver disease]. Korean J Hepatol 2009 Mar; 15(1): 42-51. 40. Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, Eisele S, Stickel F, Longerich T, Schirmacher P, Seitz HK. Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol 2010 Feb 28; 16(8): 966-972. Figure 11 Figure 13 Various results, parameters that alter with cirrhosis, probablity, statistical approach, should not forget that a single patient is treated I am aware of the manifold literature recently with statistical apporaches, LS is an objective parameters such as temperature THE INTERNATIONAL LIVER CONGRESSTM 2012 71 72 POSTGRADUATE COURSE SYLLABUS Figure 14 ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 Figure 16 Figure 15 Figure 17 THE INTERNATIONAL LIVER CONGRESSTM 2012 73 74 POSTGRADUATE COURSE SYLLABUS REFERENCES BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE Roulot D, Costes JL, Buyck JF, Warzocha U, Gambier N, Czernichow S, et al. Transient elastography as a screening tool for liver fibrosis and cirrhosis in a community-based population aged over 45 years. GUT 2011;60:977-984. Hock B SM, Domke I, Grunert VP, Wuertemberger M, Schiemann U, Horster S, Limmer C, Stecker G, Soyka M. Validity of carbohydrate-deficient transferrin (%CDT), gamma- glutamyltransferase (gamma-GT) and mean corpuscular erythrocyte volume (MCV) as biomarkers for chronic alcohol abuse: a study in patients with alcohol dependence and liver disorders of non-alcoholic and alcoholic origin. Addiction 2005;100:1477-1486. Bell H TC, Try K, Haug E. Carbohydrate-deficient transferrin and other markers of high alcohol consumption: a study of 502 patients admitted consecutively to a medical department. Alcohol Clin Exp Res 1994;18:1103-1108. Seitz HK. Additive effects of moderate drinking and obesity on serum gamma-glutamyl transferase. Am J Clin Nutr 2006;83:1252-1253. Ferenci P, Dragosics B, Pesendorfer FX, Schubert H. [Gamma-glutamyl-transpeptidase in alcoholic liver diseases]. Acta Med Austriaca 1976;3:50-54. Cohen JA, Kaplan MM. The SGOT/SGPT ratio--an indicator of alcoholic liver disease. Dig Dis Sci 1979;24:835-838. Helander A, Tabakoff B. Biochemical markers of alcohol use and abuse: experiences from the Pilot Study of the WHO/ISBRA Collaborative Project on state and trait markers of alcohol. International Society for Biomedical Research on Alcoholism. Alcohol Alcohol 1997;32:133-144. Zoli M, Cordiani MR, Marchesini G, Iervese T, Labate AM, Bonazzi C, et al. Prognostic indicators in compensated cirrhosis. Am J Gastroenterol 1991;86:1508-1513. Sasso M, Miette V, Sandrin L, Beaugrand M. The controlled attenuation parameter (CAP): A novel tool for the non-invasive evaluation of steatosis using Fibroscan((R)). Clin Res Hepatol Gastroenterol 2011. d’Assignies G RM, Khiat A, Lepanto L, Chagnon M, Kauffmann C, et al. Noninvasive quantitation of human liver steatosis using magnetic resonance and bioassay methods Eur Radiol 2009;19 2033-2040. Mancini M PA, Annuzzi G, Liuzzi R, Giacco R, Medagli C, Cremone M, Clemente G, Maurea S, Riccardi G, Rivellese AA, Salvatore M. Sonographic hepatic-renal ratio as indicator of hepatic steatosis: comparison with (1)H magnetic resonance spectroscopy. Metabolism 2009;58:1724-1730. Ratziu V BS, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010;53:372-384. Mueller S, Sandrin L. Liver stiffness: a novel parameter for the diagnosis of liver disease Hepatic Medicine: Evidence and Research 2010;2:49-67. Castera L. Non-invasive assessment of liver fibrosis in chronic hepatitis C. Hepatol Int 2011; 5:625-634. Naveau S GG, Asnacios A, Agostini H, Abella A, Barri-Ova N, Dauvois B, Prevot S, Ngo Y, Munteanu M, Balian A, Njike-Nakseu M, Perlemuter G, Poynard T. Diagnostic and prognostic values of noninvasive biomarkers of fibrosis in patients with alcoholic liver disease. Hepatology 2009;49:97-105. Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly JP, et al. Assessment of asymptomatic liver fibrosis in alcoholic patients using fibroscan: prospective comparison with seven non-invasive laboratory tests. Aliment Pharmacol Ther 2008;28:1188-1198. Rosenberg WM VM, Thiel R. Becka M, Burt A, Schuppan D, Hubscher S, Roskams T, Pinzani M, Arthur MJ. Serum markers detect the presence of liver fibrosis: a cohort study. Gastroenterology 2004;127:1704-1713. THE INTERNATIONAL LIVER CONGRESSTM 2012 75 Lieber CS WD, Morgan TR, Paronetto F. Aspartate aminotransferase to platelet ratio index in patients with alcoholic liver fibrosis. Am J Gastroenterol 2006;101:1500-1508. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001;357: 1069-1075. Naveau S, Raynard B, Ratziu V, Abella A, Imbert-Bismut F, Messous D, et al. Biomarkers for the prediction of liver fibrosis in patients with chronic alcoholic liver disease. Clin Gastroenterol Hepatol 2005;3:167-174. Cales P OF, Michalak S, Hubert-Fouchard I, Rousselet MC, Konate A, Gallois Y, Ternisien C, Chevailler A, Lunel F. A novel panel of blood markers to assess the degree of liver fibrosis. Hepatology 2005;42:1373-1181. Parkes J RP, Harris S, Day C, Mutimer D, Collier J, Lombard M, Alexander G, Ramage J, Dusheiko G, Wheatley M, Gough C, Burt A, Rosenberg W. Enhanced liver fibrosis test can predict clinical outcomes in patients with chronic liver disease. GUT 2010;59:1245-1251. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705-1713. Castera L PM. Biopsy and non-invasive methods for the diagnosis of liver fibrosis: does it take two to tango? GUT 2010;59:861-866. Boursier J, Konate A, Guilluy M, Gorea G, Sawadogo A, Quemener E, et al. Learning curve and interobserver reproducibility evaluation of liver stiffness measurement by transient elastography. Eur J Gastroenterol Hepatol 2008;20:693-701. Kazemi F, Kettaneh A, N’Kontchou G, Pinto E, Ganne-Carrie N, Trinchet JC, et al. Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices. J Hepatol 2006;45:230-235. Castera L, Bail BL, Roudot-Thoraval F, Bernard PH, Foucher J, Merrouche W, et al. Early detection in routine clinical practice of cirrhosis and oesophageal varices in chronic hepatitis C: Comparison of transient elastography (FibroScan) with standard laboratory tests and non- invasive scores. J Hepatol 2009;50:59-68. Janssens F, de Suray N, Piessevaux H, Horsmans Y, de Timary P, Starkel P. Can Transient Elastography Replace Liver Histology for Determination of Advanced Fibrosis in Alcoholic Patients: A Real-life Study. J Clin Gastroenterol. Mueller S, Millonig G, Sarovska L, Friedrich S, Reimann FM, Pritsch M, et al. Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol 2010;16:966-972. Nahon P, Kettaneh A, Tengher-Barna I, Ziol M, de Ledinghen V, Douvin C, et al. Assessment of liver fibrosis using transient elastography in patients with alcoholic liver disease. J Hepatol 2008;49:1062-1068. Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008;47:380-384. Sagir A, Erhardt A, Schmitt M, Haussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2008;47:592-595. Lanzi A, Gianstefani A, Mirarchi MG, Pini P, Conti F, Bolondi L. Liver AL amyloidosis as a possible cause of high liver stiffness values. Eur J Gastroenterol Hepatol 2009. Millonig G, Friedrich S, Adolf S, Fonouni H, Golriz M, Mehrabi A, et al. Liver stiffness is directly influenced by central venous pressure. J Hepatol 2010;52:206-210. Millonig G, Reimann FM, Friedrich S, Fonouni H, Mehrabi A, Buchler MW, et al. Extrahepatic cholestasis increases liver stiffness (FibroScan) irrespective of fibrosis. Hepatology 2008;48: 1718-1723. Gelsi E, Dainese R, Truchi R, Marine-Barjoan E, Anty R, Autuori M, et al. Effect of detoxification on liver stiffness assessed by fibroscan((R)) in alcoholic patients. Alcohol Clin Exp Res 2011;35:566-570. 76 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE ABUSE OR DEPENDENCE? ASSESSING THE ALCOHOLIC PATIENT IN THE CLINIC Antoni Gual Barcelona, Spain E-mail: [email protected] KEY POINTS • Alcohol is the most dangerous drug when self inflicted harm and harm to others are considered, and is the second top risk factor for health in developed countries. • Europe is the region of the world with the highest alcohol consumption. • Hazardous and harmful drinking are defined taking the amounts drunk into account, and people experiencing alcohol related harm do not need to be alcoholics. • The new DSM V (to be released May 2013), will probably combine Abuse and Dependence in a single entity called alcohol use disorders (AUD) of graded severity. • The criteria that define AUD cover four different areas: biological processes, medical harm, behaviour and social & relational aspects. All of them must be assessed carefully in alcoholic patients. • The assessment of AUD must be done in an empathic non judgmental attitude, and must include a careful examination of drinking patterns, and an evaluation of the bio-medical, behavioural and social consequences of AUD. INTRODUCTION According to recent studies (Nutt, 2010), alcohol is the most dangerous drug when self inflicted harm and harm to others are considered. Despite this evidence, Europe continues to be the region of the world with highest alcohol consumption. The World Health Organization (WHO) places alcohol as the second top risk factor for health in developed countries. 9 % of the disability adjusted life years in Europe are attributable to alcohol. Figure 1 BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 77 There is general agreement in the scientific community that the magnitude of the problems created by alcoholic beverages to society deserves a public health approach. From the medical point of view, alcohol is related to no less than sixty diseases, and it is wll known from ancient times that the liver is one of the most vulnerable targets. DEFINING HAZARDOUS & HARMFUL DRINKING Most of the people who drink alcoholic beverages do it at very low risk levels, but a relevant percentage of the drinkers may be at risk or experience problems because of their drinking. According to WHO hazardous drinkers are defined as those whose level of consumption or pattern of drinking is likely to result in harm should present drinking habits persist (Babor et al. 1994). There is no standardized agreement for the level of alcohol consumption that should be taken for hazardous drinking, and for many conditions any level of alcohol consumption can carry risk. A working definition of the WHO describes it as a regular average consumption of 20g-40g of alcohol a day for women and 40g60g a day for men (Rehm et al. 2004). Harmful drinking is defined as .a pattern of drinking that causes damage to health, either physical (such as liver cirrhosis) or mental. Based on the epidemiological data relating alcohol consumption to harm the WHO defines operatively harmful alcohol consumption as a regular average consumption of more than 40g alcohol a day for women and more than 60g a day for men (Rehm et al 2004). Episodic heavy drinking is defined as a drinking occasion that includes consumption of at least 60g of alcohol, and it is considered a form of hazardous drinking that quite often leads to harm. Hazardous and harmful drinking are defined taking the amounts drunk into account, and people experiencing alcohol related harm do not need to be alcoholics. The American Psychiatric Association (APA) uses the term Alcohol Abuse, which is often used as a synonimous of hazardous and harmful drinking. DIAGNOSING ALCOHOL DEPENDENCE The diagnosis of alcohol abuse is mostly based on the amounts drunk and in the presence of harm. Instead, alcohol dependence is defined takiing into account the drinking patterns of the patient and the type of relationship the patient has stablished with alcohol. The presence of tolerance, withdrawal signs and the salience of drinking behaviour over other priorities (family, work, health) are key to stablish a diagnosis. Both the APA and the WHO have set very similar criteria to diagnose alcohol dependence (Figure 2), and in both cases the presence of 3 or more criteria during the last 12 months is taken as cut-off to stablish the diagnosis. As it can be seen in Figure 1 the criteria used by WHO and APA are pretty similar, and so it is quite likely that the new versions of ICD and DSM will merge in a common definition. Figure 2 78 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE A NEW CONCEPTUAL UMBRELLA: ALCOHOL USE DISORDERS Even though it will not be launched until May 2013, the new DSM V is at an advanced status and just slight changes may be expected from now until its release (O’Brien, 2011). The working draft that is available proposes relevant changes concerning addiction to substances. Abuse and Dependence will now be combined in a single entity of graded severity: the Alcohol Use Disorder (AUD). This integrated entity is defined with 11 criteria, which in fact merge the criteria previously used to define dependence and abuse., and it is expected that the future ICD-11 will also converge to this definition (see Figure 3). Figure 3 BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 79 THE ART OF ASSESSING ALCOHOL DEPENDENT PATIENTS: WHAT TO ASSESS AND HOW TO DO IT Drinking patterns should be assessed carefully in alcohol dependent patients both quantitatively and qualitatively. Amounts drunk per week and amounts drunk per drinking occasion should be registered using standard drink units (SDU). SDU vary from country to country. In most EU countries they range between 8-10 grams, while in north America their range is 13-14 grams of pure alcohol per SDU. In alcohol dependent patients, the use of other drugs, including tobacco and benzodiazepines, should also be routinely assessed. In very defensive patients direct inquiries on their alcohol consumption may lead to relevant underestimates of their drinking. In those cases a ‘normal day assessment strategy’ is recommended, which consists of asking for a detailed descriptions of the activities performed during a normal day, where questions on drinking are imbedded. There are various validated tools that may be used for screening. The AUDIT (Alcohol Use Disorders Identification Test; Babor et al, 2001) is the actual golden standard. It has been validated to many languages and has different cut-off values for hazardous drinking and alcohol dependence. The biomedical assessment of alcohol dependent patients is very important not only because medicalisation increases adherence to treatment, but because those patients usually present with a diversity of medical problems. Alcohol is related to no less than 60 illnesses. a focussed anamnesis is required, and special attention must be devoted to casualties, since they are very frequent. A blood test including liver enzymes is also required. Most of the harm produced by alcohol is in the mental health area. Assessment of mental health status must include the identification of alcohol-related psychological distress (ie: guilt feelings, insomnia, irritability, anxiety, disruptive behaviour, etc) as well as the assessment of psychiatry co morbidity usually found in alcoholics: depression, anxiety disorders, personality disorders, etc. Special attention must be placed on suicidal thoughts and suicidal attempts, since there is strong evidence of the links between alcohol and suicide. A second major change is that the number of criteria needed to qualify for a ‘moderate’ AUD is 2-3, while a ‘severe’ AUD will be diagnosed to patients fulfilling 4 or more criteria. A third major change is that the presence of physiological dependence (tolerance, withdrawal) wil be identified separately. This new scenario will raise the prevalence of AUD (compared to alcohol dependence) and will place higher requirements on the clinicians in order to differentiate severe and moderate AUD, as well as the identification of physiological dependence, based on the presence of tolerance and/or withdrawal signs. The criteria that define AUD cover four different areas: biological processes, medical harm, behaviour and social & relational aspects. All of them must be assessed carefully in alcoholic patients (Figure 4). Figure 4 The assessment of the social consequences of alcohol can often be done without attributing them to alcohol. Family problems (including domestic violence), instability at work, financial difficulties and legal antecedents (driving while intoxicated offences, aggressions, etc) are not uncommon. It is usually helpful to conduct the assessment in the presence of a close relative. Even though this strategy may preclude the patient to give some relevant information, in general it will provide more objective data on the severity of the problems experienced. Since alcoholics are often quite defensive, assessment must be conducted in a very empathic and nonjudgmental attitude. Alcoholics tend to explain in detail ‘why’ things happened, but usually give scarce information on ‘what’ actually happened. Clinicians should stick to the facts and avoid the trap to discuss the reasons why things happened. SUMMARY The AUD is now seen as a single entity with graded levels of severity, and with a qualitative (taxonic) change at the severe end of the spectrum, where tolerance and withdrawal signs are present. The assessment of alcohol use disorders must be done in an empathic non judgmental attitude, and must include a careful examination of drinking patterns, and an evaluation of the bio-medical, behavioural and social consequences of AUD. 80 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE REFERENCES American Psychiatric Association (2004) Diagnostic and Statistical Manual of Mental Disorders. Fourth Edition. Text revision. American Psychiatric Association. Washington DC. Babor, T.F., Higgins-Biddle, J.C. (2001) Brief Intervention For Hazardous and Harmful Drinking A Manual for Use in Primary Care Geneva: World Health Organization WHO/MSD/MSB/01.6b. Babor, T., Campbell, R., Room, R. & Saunders, J., eds. (1994) Lexicon of Alcohol and Drug Terms, World Health Organization, Geneva. Rehm J, Room R, Monteiro M, Gmel G, Graham K, Rehn T, Sempos CT, Frick U, Jernigan D. (2004) Alcohol. In: WHO (ed), Comparative quantification of health risks: Global and regional burden of disease due to selected major risk factors. Geneva. WHO. Nutt DJ, King LA, Phillips LD; Independent Sci. Committee on Drugs. (2010) Drug harms in the UK: a multicriteria decision analysis. Lancet. Nov 6;376(9752):1558-65. O’Brien C. (2011) Addiction and dependence in DSM-V. Addiction. May;106(5):866-7. World Health Organization (1992) The ICD-10 Classification of Mental and Behavioural Disorders: Clinical Descriptions and Diagnostic Guidelines. Geneva: World Health Organization. World Health Organization (2009) Global health risks: mortality and burden of disease attributable to selected major risks. World Health Organization, Geneva. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 81 MANAGEMENT OF ALCOHOL DEPENDENCE IN PATIENTS WITH ALD Giovanni Addolorato Rome, Italy E-mail: [email protected] KEY POINTS • In patients with alcohol liver disease (ALD), persistent alcohol intake is associated with disease progression, therefore the most effective recommendation for these individuals is total alcohol abstinence. • In alcohol dependent patients, disulfiram, naltrexone and acamprosate, combined with counseling, represent effective medications in reducing alcohol consumption and preventing relapse and they are both approved for this indication. It should kept in mind that naltrexone and disulfiram are not recommended in patients with ALD and that there are no data on the safety of acamprosate in patients with ALD. • Topiramate and baclofen may represent potential novel alcohol pharmacotherapies, but they are not approved for this indication. To date, baclofen represents the only alcohol pharmacotherapy tested in alcoholics with ALD (i.e. alcohol-dependent patients with cirrhosis). INTRODUCTION Alcohol use disorders (alcohol abuse and dependence) is a chronic, relapsing condition with a multifactorial etiology that includes genetic, neurobiological, psychological, and environmental components. Protracted behaviour modification, cognitive behavioural therapy, psychological counseling, and mutual support groups (eg, Alcoholic Anonymous) have been considered the most effective long-term treatments. However, increasing knowledge of the neurobiological mechanisms underlying the development and persistence of addiction has led to wider recognition of alcohol addiction as a clinical disorder. In particular, specific brain neurotransmitter systems associated with alcohol craving and addiction have been identified. Accordingly, treatment has progressed from social and behavioural approaches alone to ‘adjunct’ pharmacotherapy interventions and since the 1980s, the number of medications found to be potentially effective in treating alcohol craving and dependence has increased. In particular before the discovery of anti-craving drugs, the administration of disulfiram and surveillance by relatives and/or therapeutic groups, waiting for spontaneous craving exhaustion, were the only treatment strategies to control craving. In the last decades, several drugs able to interfere with the neurotransmitters involved in craving mechanisms have been experimented (Addolorato et al, Neuropsychobiology), showing their efficacy to increase abstinence and to prevent relapse. MAIN ANTI-CRAVING DRUGS Naltrexone Naltrexone is an opioid receptor antagonist. The use of naltrexone in alcohol-dependent patients is based on the involvement of the opioid system in the compulsive desire for alcohol. In animal model, naltrexone abolishes the alcohol deprivation effect demonstrating its anti-relapse properties and, consequently, its anti-craving action. In humans, naltrexone, at a dose of 50 mg/day, has shown its efficacy in decreasing the compulsive component of alcohol craving and in increasing the compliance to alcohol-detoxification programs. A double-blind placebo-controlled study by Volpicelli et al.(1992) showed that the administration of naltrexone to alcoholic patients decreases relapses by means of the reduction in the number of heavydrinking days. Most studies found no significant difference in the occasional intake of alcohol (‘slips’) between patients treated with naltrexone and with placebo; however, patients treated with naltrexone showed a significantly lower percentage of full relapse compared with patients treated with placebo. Obviously, the efficacy of the drug is increased when the treatment is combined with a specific psychological support, in 82 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE particular supportive and coping skills therapy. Naltrexone is also effective in decreasing alcohol desire caused by images of alcoholic beverages. It also decreases alcohol intake in social drinkers, hazardous drinkers and ‘problematic’ drinkers susceptible to risk situations. The efficacy of naltrexone in the treatment of alcohol dependence or abuse in patients with complete participation in the treatment, including the psychosocial management, was also shown in multicenter studies. However, two recent well-performed placebo-controlled studies have shown low efficacy or no efficacy of naltrexone in treating patients with alcohol problems. More recently, naltrexone was copared and combined with acamprosate. Naltrexone, acamprosate and the combined medication were significantly more effective than placebo. Moreover, naltrexone-treated patients showed a better outcome regarding time to first drink and time to relapse. The combined medication was most effective with significantly lower relapse rates than placebo and acamprosate but not lower than naltrexone. Finally, a recent comparative study between gammahydroxybutyric acid (GHB) and naltrexone showed that GHB is more effective that naltrexone in treating alcohol addiction once remission of the withdrawal syndrome has been achieved if the main outcome is to maintain abstinence; on the other hand, the study confi rmed that naltrexone is useful in preventing alcohol relapse in heavy drinking. In conclusion, naltrexone could be effective in treating patients with the need for reward as the main component of alcohol craving, while GHB (see below) could be effective in treating patients with the need for relief as the main component of alcohol craving. Side effects include nausea (10% and self limiting) and, less frequently, headache, dizziness, insomnia, vomiting, anxiety and sleepiness. The incidence of side effects increases if the patient does not abstain from alcohol. Naltrexone should not be administered to patients with acute hepatitis or liver impairment. Acamprosate Even if the mechanism of action is not completely known, it seems that acamprosate affects calcium channels with a subsequent decrease in the activity of the excitatory system in the central nervous system. Acamprosate administration in alcohol-preferring rats causes a significant decrease in alcohol intake and an increase in glutamate, taurin and GABA basal concentrations in the hypothalamus and nucleus accumbens. Acamprosate may therefore provide a protective mechanism against neurotoxicity, in particular by reducing the excitatory amino acid glutamate. Animal studies have also shown the anti-relapse properties and the anti-craving action of the acamprosate. Double-blind clinical trials in alcoholic patients (1.3–3 g/day, orally administered) have shown the efficacy of acamprosate in decreasing alcohol craving and maintaining abstinence. Studies performed in a large number of alcohol-dependent patients showed that acamprosate reduces the rate of episodes of ‘relapse’ and increases the number of alcohol-free days. However, in this case a recent study showed a low efficacy of the drug in treating alcoholic patients. From this point of view, it is important to consider the typology of the patient; in particular, recent evidence indicates that acamprosate is effective in increasing sobriety times, but only in some typology of patients (i.e. Lesch type I and II patients). Finally, a recent meta-analysis study showed that acamprosate has a significant beneficial effect in enhancing abstinence in newly detoxified, alcohol-dependent patients. Acamprosate could be effective in treating patients with relief craving. Gamma-Hydroxybutyric Acid GHB is an endogenous compound with neuromodulatory functions. It has an alcohol-mimetic effect on the central nervous system. This substance interferes with some neurotransmitter systems, in particular with the mesolimbic-cortical system, by inducing variations in dopamine, serotonin and GABA cerebral concentrations. Both preclinical and clinical studies have shown that GHB is effective in the treatment of alcohol dependence. Besides its effectiveness in the treatment of alcohol withdrawal syndrome with efficacy equivalent to diazepam and clomethiazole, GHB (50 mg/kg body weight, divided into three daily doses) decreases alcohol craving by reproducing rewarding effects and thus also reducing the number of episodes of ‘relapse’. GHB is well tolerated; transient side effects, including dizziness, hyporeflexia and somnolence, have been reported. Non therapeutic use of GHB can produce an anabolic side effect, BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 83 but the latter has not been reported in alcoholic patients at the therapeutic dose. Because of its alcoholmimicking effect, cases of GHB craving and the consequent risk of GHB abuse and dependence have been reported in the course of GHB treatment; however this phenomenon is relatively rare. Up to 30–40% of alcohol-dependent patients do not respond to GHB treatment, the short half-life of the drug (about 2 h) being considered a possible cause. Recent studies have shown that nonresponders to the conventional fractioning into 3 daily doses of GHB seem to benefit from the subdivision into 6 daily doses at the same total amount (50 mg/kg body weight/day). In these patients, the increased dose fractioning seems to be able to cause a significant reduction in craving, increasing the therapeutic efficacy and decreasing the risk of abuse. These results have also been confirmed in animal studies. GHB could be effective in treating patients with reward and/or relief craving Baclofen Baclofen is a selective GABAB receptor agonist. Baclofen is well-absorbed after oral administration and undergoes little liver metabolism (B15%), being primarily eliminated by renal excretion; about 85% of a single oral dose is excreted unchanged in the urine. Preclinical pharmacological and behavioral data indicate that baclofen effectively suppresses alcohol withdrawal symptoms (AWS), acquisition and maintenance of alcohol drinking behaviour, relapse-like drinking, alcohol’s reinforcing, rewarding, stimulating, and motivational properties in rats and mice. The first human open-label pilot study showed the ability of baclofen (10 mg t.i.d. over 4 weeks) in reducing alcohol craving and intake in alcohol-dependent individuals. These encouraging results led the same researchers to test baclofen in a randomized, doubleblind, placebo-controlled design in which baclofen (10 mg t.i.d.) or placebo was administered for 4 weeks. Results of this study showed baclofen’s efficacy, with respect to placebo, in reducing alcohol intake, craving scores, and state anxiety, and in increasing cumulative abstinence duration. Subsequent open-label 12week pilot studies have further confirmed the role of baclofen in reducing alcohol intake and craving and anxiety scores, and promoting alcohol abstinence. In both studies, baclofen was reasonably tolerated and no serious adverse events were reported. The most common side effects were sleepiness, tiredness, and vertigo, which tended to resolve within 1–2 weeks of drug treatment. Recently, these findings were extended in a larger double blind placebo-controlled trial involving 84 alcohol-dependent patients affected by liver cirrhosis (see next paragraph). Consistent with previous observations, this study showed a significant effect of baclofen (10 mg t.i.d.), compared with placebo, in reducing alcohol craving and intake and in promoting total alcohol abstinence. All studies reported above tested baclofen at a dose of 10 mg t.i.d. However, the safety and the manageability of baclofen led researchers to test baclofen at higher doses. The role of different doses of baclofen (10 mg or 20 mg t.i.d.) in alcohol dependence has been explored in a randomized double-blind placebocontrolled 12-week trial. The effect of baclofen 20 mg t.i.d. was significantly higher than that of baclofen 10 mg t.i.d., showing a dose–effect relationship. Both doses of baclofen were well tolerated. The role of baclofen has also been reported in the management of AWS. A randomized study compared baclofen (10 mg t.id. for 10 consecutive days) with the ‘gold standard’ diazepam (0.5–0.75 mg/kg/day) in the treatment of moderate to severe AWS, showing a comparable efficacy of the two drugs in reducing AWS symptoms. Additional preliminary evidence further confirms these observations: a chart review showed that baclofen prevented the development of AWS symptoms, and a placebo-controlled randomized study, where subjects with AWS received baclofen 10 mg t.i.d. or placebo, showed that the need for benzodiazepines to control symptoms of AWS was significantly lower in the baclofen group. In conclusion, considering its efficacy in the management of AWS, in reducing alcohol craving, and in promoting alcohol abstinence, baclofen might be considered a promising new drug for the treatment of alcohol dependence, particularly in alcoholic patients with alcoholic liver disease. However, larger studies are needed to confirm the present findings and to expand the information on the safety of higher doses of baclofen in the treatment of alcohol dependence. 84 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Topiramate Topiramate, a sulfamate-substituted fructose-1,6-diphosphate analog with strong anticonvulsant properties, increases GABAA-facilitated neuronal activity and also antagonizes AMPA and kainite glutamate with a consequent reduction of dopamine release in the nucleus accumbens. Topiramate has an almost complete oral absorption with high bioavailability (80%). The drug is not widely metabolized and is predominantly eliminated (70%) unchanged in the urine (Shank et al, 2000). Several studies suggest a role for topiramate in treating alcohol use disorders, although further studies are needed to confirm the present findings. The first clinical trial with 150 alcohol-dependent patients showed topiramate’s efficacy in reducing alcohol dependence and promoting abstinence. In this trial, topiramate was significantly more effective than placebo in reducing drinking variables (drinks per day, drinks per drinking day, percentage of heavy drinking days, plasma g-glutamyl transferase ratio), and in increasing the percentage of abstinent days. Topiramate was effective in reducing some craving measurements (i.e. obsessive thoughts about alcohol, automaticity of drinking, interference due to drinking). No serious adverse events were reported during the trial (Johnson et al, 2003). These results were confirmed in a larger 14-week clinical trial with 371 alcohol-dependent patients and performed across 17 US sites. In addition to confirming the efficacy of topiramate on alcohol drinking, this trial also showed effects of topiramate on physical health, alcohol craving, and psychosocial wellbeing. Outcome measures of physical health included liver function tests, hematological, and biochemical measures (plasma cholesterol and bicarbonate and urine pH level), vital signs (blood pressure, pulse, and temperature), and BMI. Topiramate was superior to placebo in improving physical health outcomes and measures of psychosocial functioning. Altogether, these results suggest that topiramate has greater efficacy than placebo to improve the quality of life, decrease the severity of alcohol dependence, and reduce the detrimental consequences associated with heavy drinking. Future research may include the combination of topiramate with other medications, as well as the identification of endophenotypes with different responses to topiramate-induced side-effects. Fluoxetine, Other Serotonin Reuptake Inhibitors and Ondansetron Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), seems to act also through GABA-ergic action as well as with serotoninergic mechanisms; it is administered at a dose of 20 mg/day for the fi rst 2 days with a subsequent dose of 60 mg/day, taking care to note the possible occurrence of manic reactions . Recent studies have shown the efficacy of fluoxetine in alcoholic patients affected by depression; at a dose of 20 mg/day for the fi rst 2 weeks then 40 mg/day if necessary, fluoxetine has proved to be effective in reducing depressive symptoms and alcohol consumption in these patients . Its efficacy, however, seems to decrease in alcoholic patients without significant mood disorders. Fluvoxamine is a monocyclic SSRI, registered worldwide for the treatment of depression and obsessive compulsive disorders. A double-blind multicenter study showed no evidence that this drug helps prevent relapse in detoxified, abstinent or alcoholic patients. There are some contrasting data on the efficacy of sertraline, citalopram (SSRI agents). It seems that SSRIs might be useful in late-onset alcoholics, while ondansetron at a dose of 0.5–4 mg divided into two daily doses for 6 weeks could be effective in early-onset alcoholics. Ondansetron (5HT3 receptor antagonist) is able to increase dopamine level throughout the blocking action on 5HT3 receptor. This drug seems to be effective to reduce craving and alcohol intake in early-onset alcoholics; moreover recent data showed the efficacy of ondansetron in some genetic subtype of alcoholic patients. MEDICAL MANAGEMENT OF ALCOHOL DEPENDENCE IN PATIENTS WITH ALD Alcoholic liver disease (ALD) is one of the major medical complications of alcohol abuse. In particular, 80% of heavy drinkers develop steatosis, 10–35% develop alcoholic hepatitis, and approximately 10% will develop cirrhosis. Possible factors that affect the development of liver injury include the dose, duration, and type of alcohol consumption, drinking patterns, gender, ethnicity, and associated risk factors including obesity, iron overload, concomitant infection with viral hepatitis, and genetic factors. In addition to dietary supplement therapy, several drugs have been tested to improve survival in patients with ALD, including corticosteroids, propylthiouracil, S-adenosyl-L-methionine, infliximab and pentoxifylline. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 85 However, independent of the stage of ALD, abstinence from alcohol is the cornerstone of management, since medical and surgical treatments for ALD have limited success when drinking continues. Accordingly, total alcohol abstinence can improve the histology and/or survival of individuals with ALD and the clinical outcome of all stages of ALD. On the contrary, persistent alcohol intake induce progression of liver damage and, in those patients with alcoholic cirrhosis, is associated with a significant risk ratio of death due to bleeding esophageal varices, infection, renal failure, and/or hepatic failure. Psychological approach and counselling are essential components of therapy to promote abstinence in these patients. However the efficacy of group and supportive psychotherapy is relatively low as monotherapy (15-39%). As reported above, at present there are several medications able to reduce alcohol craving and, consequently, to increase abstinence and prevent alcohol relapse. However trials investigating anti-craving medications typically exclude individuals with high levels of transaminases and/or advanced liver disease, for the concern that these medication might worsen liver disease. Infact, naltrexone is contraindicated in those with liver disease due to its hepatic metabolism and reports of medication-related hepatic injury. Acamprosate may induce hyperammoniemia; topiramate affect liver function and it may also induce hyperammoniemia. In the last few years, growing evidences suggest a role of baclofen in the management of ALD patients; at present baclofen is the only drug tested in alcohol dependent patients affected by liver cirrhosis or acute alcoholic hepatitis. Based on the safe profile of baclofen, summarized before, and considering baclofen’s pharmacological profile (renal excretion and a small liver metabolism), a first randomized clinical trial was conducted with a population of alcohol-dependent patients affected by liver cirrhosis. Inclusion criteria consisted of both a current diagnosis of alcohol dependence and a diagnosis of cirrhosis. In this trial, baclofen (10 mg t.i.d.) or placebo was administered for a 12-week period. Baclofen showed a significant effect, compared to placebo, in reducing alcohol intake and craving. In particular, a significantly higher number of patients treated with baclofen achieved and maintained abstinence (71.4%) compared to the placebo group (28.6%; p=0.0002). The number of drop-outs was not statistically significantly different between baclofen group (14.3%) and placebo group (31%; p=0.12). Cumulative Abstinence Duration was approximately two-fold higher in baclofen- than placebo treated patients (p=0.001). Survival analysis revealed a significantly greater chance in the baclofen group of remaining free of relapse to alcohol consumption (p=0.006). There was also a significant reduction of OCDS craving scores (OCDS total score and obsessive and compulsive OCDS subscores) in the baclofen group compared to the placebo group. No patients had encephalopathy during the study period. Further, none showed hyperammonaemia or significant changes in number connection test performance. Individuals allocated baclofen had significantly reduced alanine aminotransferase, bilirubin, international normalised ratio, and γ glutamyltransferase from baseline and significantly increased albumin. No serious systemic or single-organ event leading to drug cessation was reported and no patient discontinued treatment because of a side-effect. Tolerability was fair in all individuals. The safety of baclofen in patients with alcoholic liver disease has been confirmed by a further study where baclofen was administered for at least 5 months in 14 patients with alcoholic hepatitis (Avanesyan and Runyon, 2010). In this trial 13/14 patients completely stopped drinking/craving alcohol since the start of baclofen and one patient reported a reduction in alcohol consumption from 50 to 3 drinks/ day. Those with the most severe illness were more willing to comply with medication, thus, showing the most improvement. Total bilirubin was notably reduced. About 70% reduction was observed at 5 months and 90% reduction after 8 months of baclofen use. Reduction in total bilirubin and AST were statistically significant. No side effects were reported. In conclusion baclofen, because of its anticraving action and safety, could have an important role for treatment of alcohol-dependent patients with advanced liver disease, including those needing liver transplantation (OLT), since the need of alcohol abstinence both before and after OLT. 86 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE REFERENCES Addolorato G, Abenavoli L, Leggio L, Gasbarrini G (2005). How many cravings? Pharmacological aspects of craving treatment in alcohol addiction: a review. Neuropsychobiology, 51:59-66. Addolorato G, Leggio L (2010). Safety and efficacy of baclofen in the treatment of alcohol- dependent patients. Curr Pharm Des, 16:2113-2117. Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G (2007). Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 370: 1915–1922. Addolorato G, Leggio L, Hopf FW, Diana M, Bonci A (2011). Novel therapeutic strategies for alcohol and drug addiction: focus on GABA, Ion channels and transcranial magnetic stimulation. Neuropsychopharmacology, doi: 10.1038/npp.2011.216. [Epub ahead of print] Altamirano J, Bataller,R. (2011). Alcoholic liver disease: pathogenesis and new targets for therapy Nat Rev Gastroenterol Hepatol, 8:491-501 Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K Ait-Daoud N, Addolorato G, Anton RF, Ciraulo DA, Kranzler HR, Mann K, O’Malley SS, Swift RM,Topiramate for Alcoholism Advisory Board; Topiramate for Alcoholism Study Group (2008). Improvement of physical health and quality of life of alcohol dependent individuals with topiramate treatment: US multisite randomized controlled trial. Arch Intern Med, 168: 1188–1199. Koob GF, Volkow ND (2010). Neurocircuitry of addiction. Neuropsychopharmacology 35: 217–238 Lucey MR, Mathurin P, Morgan TR (2009). Alcoholic hepatitis. N Engl J Med, 360:2758-2769. O’Shea RS, Dasarathy S, McCullough AJ, Practice Guideline Committee of the American Association for the Study of Liver Diseases; Practice Parameters Committee of the American College of Gastroenterology (2010). Alcoholic liver disease. Hepatology, 51:307-28 Spanagel R (2009). Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol Rev, 89: 649–705. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 87 EXTRAHEPATIC INVOLVEMENT IN PATIENTS WITH CHRONIC ALCOHOL LIVER DISEASE Joaquim Fernández-Solà Barcelona, Spain E-mail: [email protected] KEY POINTS • ALD does not involve just the liver, but is a real systemic disease. Systemic damage parallels in degree and timing that of ALD. • Extrahepatic involvement, mainly neurological, cardiovascular and nutritional, should be regularly assessed in patients with ALD. • There is a clear relationship between the degree of hepatic and systemic toxics effects of alcohol. The greater the liver damage, the greater systemic damage expected. • To improve global health status of the subjects with ALD a multidisciplinary management approach is necessary. INTRODUCTION The purpose of this presentation is to consider some aspects that make Alcohol Liver Diseases (ALD) as a real systemic disease with a clear extrahepatic involvement, in which a multidisciplinary approach is necessary. The pathogenic effects that induce liver damage and disease may also generate additional systemic organ damage through common pathogenic mechanisms. Similarly, liver is frequently involved in most systemic diseases either of infectious, toxic, metabolic, inflammatory, autoimmune or neoplastic origin. When liver disease develops in the setting of alcohol misuse (ALD), the noxious pathogenic effects locally generated in the liver also involve other organs such as heart and vascular system, bone and skeletal muscle, central and peripheral nervous system, and disrupts the nutritional status, endocrine and immune functions of the individual. Therefore, ALD usually develops in the setting of a multisystemic scenario. In fact, there is a clear relationship between the degree of hepatic and systemic toxic effects of alcohol. The final result of all these interactions determinates the global health status of the subject. Ethanol has a widespread toxic and sensitizing effect on the human body with different threshold pathological range and also with clear organ specificity according to the nature of target cells. The WHO report (2006) recognizes more than 60 diseases related to excessive alcohol consumption. Its hydrophilic and lypophilic properties confer a global body diffusion potential. Ethanol is a potent enzymatic inductor and its metabolites (acetaldehyde-acetate, FAEEs) are very active. In addition, ethanol is a pro- inflammatory agent increasing cytokine production. Individual susceptibility to EtOH depends on different factors, some of them specific (type of cell, enzymatic or metabolic factors) and others of non-specific nature (genetic, gender and environmental factors). In addition, ethanol has different synchronic and synergic effects with other pathogenic factors (toxics, nutrition, viruses) increasing its final damaging tissue effect. Liver is the major site of EtOH metabolism in the body and receive this direct noxious effect. However, other organs shared most mechanisms causing ALD. The products generated by the liver (oxidative radicals, acetaldehyde and acetate, protein adducts, cytokines, circulating antibodies) may also induce significant oxidative and inflammatory damage to other organs. This damage parallels in degree and timing that of ALD. In general, ethanol increases the lesion and decreases the cell protection mechanisms increasing 88 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE the global damage and disturbing cell repair mechanisms. The specific organ damage inflicted by EtOH depends on the final balance between damaging and local defensive host mechanisms. As it occurs in other organs, ALD is a dose-dependent disease where total lifetime and duration of alcohol consumption is highly relevant. But this process is also modulated by genetic and personal predisposing factors with organ-specific susceptibility. The systemic noxious effect of EtOH is modulated according to the characteristics of the involved cells. Thus, excitable cells such as neurons and cardiac or skeletal myocytes mainly suffer of disruption in transduction signalling systems at the level of the cytosolic membrane (receptors, channels) and organelles (mitochondria, sarcoplasmic reticulum, sarcomere). Otherwise, nonexcitable cells will receive the effect of metabolic, oxidative, inflammatory, hormonal and immune damage generated by ALD. In general, progression of alcohol-mediated tissue damage starts with non-detectable or transitory effect, followed by subclinical dysfunction without structural damage and progressing to subclinical dysfunction with structural damage. Afterwards, clinical effects appear with reversible structural damage and, finally progress to advanced clinical effects with irreversible structural damage. Relationship between ALD and systemic damage has been largely discussed. It was previously said that the presence of ALD spared the development of cardiomyopathy (CMP). However, a clear relationship between the presence and degree of hepatic and cardiac damage by EtOH has been recently corroborated. Dilated CMP is also dose-dependent. Diastolic dysfunction appears at lifetime ethanol consumption > 5 Kg/Kg in one-third of subjects, and systolic dysfunction develops in 13% of subjects with lifetime ethanol consumption > 9 Kg/Kg. If ethanol consumption is maintained, subjects develop low-output heart failure, arrhythmias and sudden death. In addition, ethanol increases the effect of other risk factors in the heart such as tobacco and cocaine. Similarly, skeletal myopathy is present in more than half of patients with liver cirrosis. It starts at subclinical level in lifetime consumption of 10Kg/Kg, and usually is clinically apparent with limb muscle weakness and atrophy in lifetime ethanol consumption >20Kg/Kg. Ethanol decreases bone density. In fact, one third of alcohol misusers develop osteoporosis in a dosedependent effect that starts at 20g/day ethanol consumption. There is an additional effect of liver disease, malnutrition and Vitamin D deficiency. Ethanol increases the risk of neurological damage In a dose-dependent manner. Hemorrhagic stroke appears at daily ethanol consumption > 60g/day (RR 2.18). Alcoholic-induced brain impairment leading to alcoholic dementia is present in 70% of alcohol misusers consuming >4 Kg/Kg. Cerebellum degeneration may be detected in 30% alcohol misusers. Wernicke’s Korsakow encephalopathy, Marchiafava-Bignami disease, central pontine myelinolysis and pellagra develops in chronic alcoholics with malnutrition, thyamin or other vitamin deficiencies and ionic disturbances. Peripheral and autonomic neuropathies develop in daily ethanol consumptions higher than 40g in women and 60 g. in men, being 20% clinically apparent and 70% subclinical, only detected by EMG Studies. THE INTERNATIONAL LIVER CONGRESSTM 2012 89 Ethanol frequently produces protein and caloric type of malnutrition and vitamin deficiencies. In fact ethanol consumption is the most important cause of malnutrition in Western Countries. Its effect has a multifactorial etiology (malabsorption, metabolic disturbances) and mainly involves high-dose ethanol consumers (>20 Kg OH/Kg). This is associated with ALD and other systemic diseases. Malnutrition clearly increases EtOH damaging effect. Therefore, malnutrition should be evaluated and corrected to decrease EtOH –induced tissue damage. ALD produces dramatic changes in redox state, episodes of oxidative stress and generates damaging products such as ROS, acetaldehyde, acetate and fatty acid ethyl esthers. These aldehydes can rapidly form covalent protein adducts that alter lipid and protein structure and play a role in derangements of hepatic, cardiac, brain and muscle function. In addition, increased levels of circulating endotoxins and proinflammatory cytokines decrease cellular defensive mechanism and induce infections and auto-inflammation. Kuppfer cells generate TNF-α and promote signalling pathways such a stress-activated-mitogen-proteinkinase (MAPK) cascade that mediates in systemic cell injury. Resistin is a intra-hepatic cytokine with proinflammatory actions in hepatic stellate cells, but also with other significant systemic effects. Insulin-like growth factor (IGF) resistance is mainly generated in ALD but producing cardiac and brain damage. Since EtOH affects immune cell functions though dendritic cell dysfunction, Kupffer cells play a key role in this process. ALD activates pro-apoptotic mechanisms with systemic noxious effects, increasing cell loss and inhibiting the possibility of tissue proliferation or repair. Also, disturbances in transcriptional mechanisms and DNA damage are frequent cause of this systemic effect of ALD. Tissue regeneration is affected by excessive alcohol, with low rate of renewal capacity in some tissues. There are common genetic predisposition conditions in ALD such is ALDH2 deficiency, that also supposes a major risk to develop CMP. In ALD, the RAS system increases fibrogenesis through angiotensin II production. Similarly, in the heart the “DD” genotype of ACE increases the risk to develop alcoholic CMP. Gender differences make women more susceptible to ALD than men, similarly to that happen for heart, muscle and nervous system damage. The presence of caloric and protein malnutrition increases the risk of EtOH-induced tissue damage. To summarize, in presence of ALD we should consider the possible development of alcohol-mediated systemic organ damage, mainly neurologic, cardiovascular and nutritional. Its development depends on the quantity and duration of alcohol consumption in each individual, but is modulated by genetic, metabolic and local tissue factors, with clear organ specificity. Since most pathogenic factors that mediate ALD also influence in widespread organ damage, ALD should be considered a systemic disease. There is direct relationship between the liver and systemic damage. The greater the liver damage the greater the systemic damage expected. Therefore, to improve global health of the subject with ALD a multidisciplinary management approach is necessary to be established. CONCLUSION ALD does not involve just the liver, but is a real systemic disease. As screening to evaluate systemic organ damage in ALD, we suggest to perform: • Heart: • Muscle: • Peripheral nerve: • Brain: • Nutrition: • Immunity: • Bone: Chest X-ray, ECG, Echosonography Strength, CK, EMG, Muscle biopsy Reflex, EMG, Muscle / Nerve biopsy Brain CT or MR, Cognitive tests Antropometric, analytic protein /vitamin profile Ig, lymphocyte subsets, Immunocomplexes X-ray, Densitometry 90 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE THE INTERNATIONAL LIVER CONGRESSTM 2012 91 NOTES CLINICAL CASE : THE ACUTELY ILL PATIENT REFERENCES: PATHOGENESIS: Cheng J.Mechanisms of Alcohol-Induced Endoplasmic Reticulum Stress and Organ Injuries. Biochem Res Int 2012; 2012: 216450. Seth D, D’Souza El-Guindy NB, Apte M, Mari M, Dooley S, Neuman M, Haber PS, Kundu GC et al. Alcohol, signaling, and ECM turnover. Alcohol Clin Exp Res 2010 34(1):4-18. Wang HJ, Zakhari S, Jung MK. Alcohol, inflammation, and gut-liver-brain interactions in tissue damage and disease development.World J Gastroenterol 2010; 16(11):1304-1313. Shimizu Y. Liver in systemic disease.World J Gastroenterol 2008; 14(26):4111-4119. HEART and SKELETAL MUSCLE: Urbano-Márquez A, Fernández-Solà J. The effects of alcohol on skeletal and cardiac muscle. Muscle Nerve 2004; 30: 689-707. Estruch R, Fernández-Solà J, Sacanella E, Paré C, Rubin E, Urbano-Márquez A. Relationship between cardiomyopathy and liver disease in chronic alcoholism. Hepatology 1995; 22: 532-538. NEUROLOGICAL DAMAGE: Harper C, Matsumoto I. Ethanol and brain damage. Curr Opin Pharmacol. 2005;5:73–78. Chopra K, Tiwari V. Alcoholic neuropathy: possible mechanisms and future treatment possibilities. Br J Clin Pharmacol 2011 Oct 11. doi: 10.1111/j.1365-2125.2011.04111.x. [Epub ahead of print] NUTRITION: Estruch R, Sacanella E, Fernandez-Solà J, Nicolas JM. Nutritional Status in Alcoholics. In: Preedy VR Ed. The Handbook of Alcohol Related Pathology. Elseiver Science Pub, London 2005; 29: 363377. Estruch R. Alcohol and Nutrition. In: Alcohol Misuse: an European perspective. MacDonald I (ed). Harward Acad Press; Oxford (UK) 1996; 41-62. Sanvisens A, Rivas I, Bolao F, Tor J, Rosón B, Rey-Joly C, Muga R. Gender and liver, nutritional and metabolic alterations of severe alcoholism: a study of 480 patients. Med Clin (Barc) 2011;137(2):49-54. BONE: Peris P, Parés A, Guañabens N, Pons F, Martínez de Osaba MJ, Caballería J, Rodés J, MuñozGómez J.Reduced spinal and femoral bone mass and deranged bone mineral metabolism in chronic alcoholics.Alcohol Alcohol. 1992; 27(6):619-625. J. Altamirano, J. Caballería Barcelona, Spain E-mail: [email protected] TOPICS: ALCOHOL WITHDRAWAL, DIAGNOSTIC AND MANAGEMENT OF ALCOHOLIC HEPATITIS, DECOMPENSATED CIRRHOSIS A 51-year-old caucasian male with arterial hypertension and no significant family history. He reported smoking 2 packs per day and drinking 8-12 beers per day for the past 20 years. One-year before the current presentation he started anti-depressive medication due to anxiety disorder. Over the previous 6 months, the patient had been unemployed and reported increased alcohol consumption (15-20 beers per day). He presented to the emergency room with malaise, new-on set jaundice, right abdominal pain, increment in the abdominal perimeter and legs edema. At admission his vital signs were: BP 100/70 mmHg , HR 105 x`, RR 22 x`, T 37.8˚C .On physical exam, the patient was noted to have conjuntival icterus, marked ascites with a prominent fluid wave and bulging flanks, bilateral pitting edema above the knees, and tender hepatomegaly. Flapping was positive on neurological examination. Significant biochemical and microbiological studies at admission are resumed in Table 1. Abdominal ultrasound revealed hepatic steatosis and no vascular or tumoral lesions were detected. Based on clinical, radiological and biochemical data diagnosis of severe alcoholic hepatitis (AH) was suspected and supportive care measures plus enteral nutrition were started. Clinical scoring systems were: Maddrey`s DF 162, MELD 33, GAHS 11 and ABIC 10.2. Initial infection screening (ascites and urine fluid analysis) was negative and blood cultures were taken. In addition, a chest-X-ray showed no pneumonia signs. He began with increased anxiety, insomnia and irritability, so clometiazol was initiated. For diagnostic confirmation a transjugular liver biopsy was performed and 24-hrs after, histological analysis revealed: macro and micro vesicular steatosis with presence moderate PNM infiltration on portal tracts, presence of hepatocyte ballooning and Mallory-Denk bodies, occasional megamitochondria, severe hepato-canallicular and ductular cholestasis and bridging fibrosis. Prednisolone PO (40mg/day) was initiated and a mild improvement on liver function tests was documented in Day 2 of hospitalization (Table 1), but 2 days later, the patient present fever (T 39˚C) with progressive dyspnea and productive cough. Blood and sputum cultures were performed. Chest radiographs revealed left lower lobe pneumonia and IV antibiotic treatment with ceftazidime (2gr TID) plus ciprofloxacin (400mg TID) was initiated. At day 7 (Table 1) the patient’s Lille score was 0.79 and corticosteroids were interrupted. In addition, a progressive and sustained increment in serum creatinine levels and deterioration in his sodium serum levels were documented (Figure 1). Patient was expanded with IV albumin for 48 hr without renal improvement and diagnosis of hepatorenal syndrome associated with infection was established. At this time, IV terlipressin (1mg every 6 hr) and albumin treatment was initiated without any improvement on renal function. At day 10 of hospitalization the patient initiated with hemodynamic deterioration and grade 3 hepatic encephalopathy. He was then admitted to ICU in where terlipressin was interrupted and norepinephrine was initiated. 24-hrs after ICU admission, the patient present exitus letalis. 92 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 93 THE ACUTELY ILL PATIENT: ALCOHOL WITHDRAWAL Table 1 WBC (109/l) Hemoglobin (gr/dl) Platelets (109/l) At admission 11.3 12.2 Day 2 11.7 100 Day 7 13.1 10.8 11 99 105 Bilirubin (mg/dl) 24 21.4 25.1 AST (UI/l) 289 243 169 ALT (UI/l) 124 101 90 GGT 653 Creatinine (mg/dl) 0.8 1.5 1.8 Albumin (gr/dl) 2.7 PT /control PT (seg) 45/15 40/15 38/15 INR 3.7 3.2 3.0 Na (mEq/l) 134 130 128 CRP (mg/L) 46 3.1 65 HBsAg Negative Anti-HCV Abs Negative Blood cultures Negative + (P. Aeruginosa) Urine cultures Negative Negative Ewan Forrest Glasgow, UK E-mail: [email protected] KEY POINTS • Alcohol misuse and dependency is common amongst general hospital admissions. • Patients with Alcoholic Liver Disease will often, but not always, be alcohol dependent. • At risk patients can be recognized with screening tools such as FAST and CAGE. • Benzodiazepines are the mainstay of treatment, but lorazepam is preferred for the treatment of patients with liver disease. • Symptom Triggered Treatment is effective for many patients but patients at high risk of severe withdrawal may require Fixed Dose Treatment. INTRODUCTION Alcohol withdrawal syndrome (AWS) arises in alcohol-dependent patients typically within 24-72 hours of having their last alcoholic drink. Features of AWS include two or more of the following: tremor, insomnia, nausea, anxiety, transient hallucinations, agitation and autonomic hyperactivity (sweating, tachycardia). In its most severe manifestations it may be complicated by withdrawal seizures or delirium tremens. This latter condition is characterized by disorientation, impaired consciousness, attention deficit, hallucinations and marked adrenergic activity. In these severe forms it is described as having a mortality of up to 20%, although with recognition and appropriate treatment this can be reduced to 1%. The management of AWS relies upon the recognition of at risk patients and the use of appropriate treatment in the most effective way. This can be especially problematic in patients who have co-existent liver disease. IDENTIFICATION OF PATIENTS AT RISK OF AWS Before effective treatment of AWS can be initiated it is vital to recognize those patients at risk. AWS is a feature of alcohol dependency and so tools designed to look for this can be used to identify such patients. Screening tools include the CAGE (cut down, annoyed, guilty and eye-opener), Short Alcohol Dependence Data (SADD/Q) and the Michigan Alcohol Screening Test (MAST) questionnaires can be used for this purpose. However recognition of hazardous/harmful alcohol consumption is also important as these patients may benefit from brief intervention and still may experience some symptoms of AWS. The Alcohol Use Disorders Identification Test (AUDIT) is a screening tool for hazardous drinking. Higher AUDIT scores have been associated with greater risk of AWS. However whilst AUDIT is effective, it is a relatively long test for use amongst general hospital admissions comprising ten separate questions. To cope with this the Fast Alcohol Screening Test (FAST) was developed. This is derived from AUDIT but is much shorter and easier to use. We have found that higher FAST values correlate well with positive CAGE questionnaires and subsequent benzodiazepine requirement. As a result we use the FAST to stratify hazardous and dependent drinking patterns in all patients admitted to general hospitals who are drinking more than the recommended limits. This allows for at risk patients to be targeted for AWS management. PREVALENCE OF ALCOHOL MISUSE The prevalence of alcohol dependency in general medical hospital admissions can be as high as 18.6% (up to 24.8% amongst male admissions). However it is incorrect to assume that all patients with alcoholic liver disease (ALD) will have alcohol dependency. In one study only 26% of patients were severely dependent drinkers on the basis of SADD assessment, with 40% having relatively low scores. In another study which excluded patients admitted primarily for complications of liver disease, patients with a history of heavy alcohol use had liver biopsies. Those with severe AWS were more likely to be binge drinkers and have evidence of alcoholic hepatitis on histology. Relatively few patients who had cirrhosis without super-added hepatitis experienced severe AWS. 94 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE MECHANISMS OF AWS The pathophysiology of AWS is related to the effects of alcohol upon neurotransmitters in the central nervous system. Prolonged alcohol exposure leads to a down-regulation of gamma-aminiobutyric acid type-A (GABAA) receptors and an up-regulation of N-methyl-D-aspartate (NMDA), which leads to the development of tolerance. During withdrawal there is reduced GABAergic transmission, enhanced NMDA, glutaminergic and adrenergic transmission and dysregulation of dopaminergic transmission. Repeated detoxification may lead to a ‘kindling’ effect with increased neuronal responsivity and increased severity of AWS and risk of seizures. The mainstay of treatment of AWS remains benzodiazepine therapy. These drugs enhance GABA activity and counteract adrenergic hyperactivity. The use of benzodiazepines also seems to reduce the kindling effect of repeated withdrawal. DRUG THERAPY FOR AWS On meta-analysis however the evidence suggests that benzodiazepines are only better than placebo in preventing alcohol withdrawal seizures. However the quality of the published trials is sub-optimal and clinical experience indicates that benzodiazepines have a more generalized beneficial effect in AWS. For most patients with AWS it is recommended that long-acting benzodiazepines such as diazepam or chlordiazepoxide are used. These agents allow a smoother course of withdrawal. Diazepam is also more lipophilic allowing rapid central nervous system distribution, however this feature also leads to re-distribution to peripheral fat in a less predictable fashion. Both diazepam and chlordiazepoxide require oxidation in the liver to produce active metabolites which themselves have long half-lives. This complex metabolism is impaired in liver disease with reduced hepatic oxidative capacity. Unpredictable metabolism and erratic drug accumulation can lead to enhanced sedation in patients with significant liver dysfunction. For this reason lorazepam is preferred in liver disease patients. This shorter acting benzodiazepine undergoes hepatic glucuronidation which is reasonably well preserved in the damaged liver. It is metabolized to an inactive product. In studies lorazepam has been shown to be equally effective to chlordiazepoxide in the management of AWS and is regarded by some s the drug of choice for the management of alcoholrelated seizures. In severe cases of AWS neuroleptic agents such as haloperidol can be used, ideally in conjunction with benzodiazepines. Chlorpromazine is best avoided as it lowers the seizure threshold. In patients with severe AWS it is necessary that there is adequate nursing supervision to monitor response to treatment and to ensure that patients do not become over-sedated and put at risk of aspiration pneumonia amongst other possible complications. In extreme cases patients may require full general anaesthesia in an intensive care setting to manage their symptoms. METHOD OF DRUG ADMINISTRATION The method of administration of benzodiazepines in AWS is controversial. Many units adhere to fixed dose treatment (FDT) regimens with set initial doses of treatment and subsequent reductions over a fixed period of time. However symptom-triggered treatment (STT) has been shown to reduce the duration and amount of benzodiazepine therapy given for AWS. The most commonly used STT instrument is the Clinical Institute of Withdrawal Assessment for Alcohol (CIWA-Ar). However the majority of studies investigating STT and comparing it with FDT have been set in specific alcohol detoxification units. There are few studies assessing CIWA-Ar in general hospital settings, and those that have frequently exclude patients with complex medical co-morbidity such as significant liver disease. Whilst an effective tool when used appropriately, the CIWA-Ar is cumbersome and is difficult to administer at the appropriate time intervals in a general ward setting. One study auditing the use of a CIWA-Ar based STT in clinical practice found that it was initiated inappropriately in 52% of cases. On multivariate analysis the presence of liver disease was the only significant factor associated with inappropriate treatment. In the light of this we stratified the majority of AWS patients into those a standard risk of severe withdrawal and those at high risk of severe withdrawal. Standard risk patients receive STT, whilst high risk patients receive FDT plus STT. Risk is assessed by the presence of high initial symptom score, high FAST score, history of alcohol related seizures and/or severe AWS in the past. Instead of CIWA-Ar we use the Glasgow BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 95 (Modified) Alcohol Withdrawal Score (GMAWS) which is less time consuming and easier to administer in a general ward setting (data awaiting publication). However there are exceptions to this approach. In particular patients with evidence of significant liver disease are managed specifically by STT (GMAWS) with lorazepam. ALTERNATIVES TO BENZODIAZEPINE THERAPY Carbemazepine prescribed in a reducing FDT fashion has been shown to be effective in managing AWS in some studies, however on meta-analysis the benefit is questionable and there is no evidence of superiority over benzodiazepines. Gamma-hydroxybutyrate (GHB) may be more effective than placebo in managing AWS but again does not appear to offer any advantage over benzodiazepines. Baclofen is another drug with potential in the management of AWS and the lack of sedating side-effects make this drug especially appealing in patients with ALD. A greater evidence base is required before these drugs can be recommended in the routine management of AWS. DIFFERENTIAL DIAGNOSIS Confusion, disorientation and agitation have a broad differential diagnosis amongst heavy drinking patients with liver disease. Care must be taken to differentiate between acute alcohol intoxication, intoxication from other substances, hepatic encephalopathy, Wernicke’s encephalopathy as well as AWS. A good clinical history (if obtainable) plus blood alcohol concentration and urine toxicology assessment will help to differentiate some of these presentations. Clinical signs such as asterixis or opthalmoplegia/nystagmus will also point to an alternative diagnosis. Clearly the prescription of benzodiazepines to patients with hepatic encephalopathy may be detrimental and so close observation of patients with liver disease treated for AWS is essential. Treatment of Wernicke’s encephalopathy with intravenous thiamine and correction of hypomagnesaemia is generally safe and should be considered in all patients presenting in this fashion. Figure 1: The FAST Screening Tool 1. MEN: How often do you have EIGHT or more drinks on one occasion? WOMEN: How often do you have SIX or more drinks on one occasion? Never 0 Less than monthly 1 Monthly 2 Weekly 3 Daily or almost daily 4 2. How often during the last year have you been unable to remember what happened the night Before because you had been drinking? Never 0 Less than monthly 1 Monthly 2 Weekly 3 Daily or almost daily 4 3. How often during the last year have you failed to what was normally expected of you because of drinking? Never 0 Less than monthly 1 Monthly 2 Weekly 3 Daily or almost daily 4 4. In the last year has a relative or friend, or a doctor or other health worker been concerned about your drinking or suggested you cut down No Yes, on one occasion Yes, on more than one occasion 0 2 4 FAST≥3 indicates hazardous drinking behavior. 96 POSTGRADUATE COURSE SYLLABUS Figure 2: Metabolism of Chlordiazepoxide, Diazepam and Lorazepam. Figure 3: The Glasgow Modified Alcohol Withdrawal Score (GMAWS) Tremor 0) No tremor 1) On movement 2) At rest Sweating 0) No sweat visible 1) Moist 2) Drenching sweats Hallucination 0) Not present 1) Dissuadable 2) Not dissuadable Orientation 0) Orientated 1) Vague, detatched 2) Disorientated, no contact Agitation 0) Calm 1) Anxious 2) Panicky Score Treatment Score: (Do not use scoring tool if patient intoxicated, must be at least 8 hours since last drink.) 0: BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE Repeat Score in 2 hours (Discontinue after scoring on 4 consecutive occasions, except if less than 48hrs after last drink) 1 – 3: Give 10mg Diazepam: Repeat Score in 2 hours 4 – 8: Give 20mg Diazepam: Repeat Score in 1 hour 9 - 10: Give 20mg Diazepam: Repeat Score in 1 hour; discuss with medical staff THE INTERNATIONAL LIVER CONGRESSTM 2012 97 REFERENCES McKeon A, Frye MA, Delanty N. The alcohol withdrawal syndrome. J Neurology Neurosurgery Psychiatry 2008; 79:854-62. Barri E, Tome S, Rodriguez I, Gude F, Sanchez-Leira J, Perez-Bacerra E, Gonzalez-Quintela A. Liver disease in heavy drinkers with and without alcohol withdrawal syndrome. Alcoholism: Clinical Experimental Research 2004; 28: 131-136. Peppers MP. Benzodiazepines for alcohol withdrawal in the elderly and in patients with liver disease. Pharmacotherapy 1996; 16: 49-57. Hecksel KA, Bostwick JM, Jaeger TM, Cha SS. Inappropriate use of symptom-triggered therapy for alcohol withdrawal in the general hospital. Mayo Clinic Proceedings 2008; 83: 274-279. Lejoyeux M, Solomon J, Ades J. Benzodiaepine treatment for alcohol-dependent patients. Alcohol Alcoholism 1998; 33: 563-575. Amato L, MMinozzi S, Davoli M. Efficacy and safety of pharmacological interventions for the treatment of alcohol withdrawal syndrome. Cochrane Database of Systematic Reviews 2011; 6: CD008537.pub2. DOI:10.1002/14651858 Doleman JM, Hawkes ND. Combining the AUDIT questionnaire and biochemical markers to assess alcohol use and risk of alcohol withdrawal in medical patients. Alcohol Alcoholism 2005; 40: 515-519. Cameron A, Morris JM, Forrest EH. The Prevalence of alcohol misuse among acute admissions: current experience and historical comparisons. Scottish Medical Journal 2006; 51: 21-23. Rogawski MA. Update on the neurobiology of alcohol withdrawal seizures. Epilepsy Currents 2005; 5: 225-230. 98 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE ALCOHOLIC HEPATITIS OR DECOMPENSATED CIRRHOSIS: DIAGNOSTIC AND PROGNOSTIC ISSUE Frederik Nevens Leuven, Belgium E-mail: [email protected] KEY POINTS • There are different types of chronic liver failure: chronic hepatic decompensation and acuteon-chronic liver failure. • Multiorgan failure occur before sepsis in ACLF and therefore scores as the SOFA score predict outcome better than MELD. • One of the most frequent precipitating events of ACLF is severe alcoholic hepatitis. • Prognostic scores used for patients with ASH are disease-specific: modified Maldrey’s discrimination function, the Lille score, the Glasgow alcoholic hepatitis score and the ABIC and the non disease-specific score: MELD. • Early control of ASH by corticosteroids prevents evolution to ACLF. • During corticosteroid treatment a Lille score at day 7 ≤ 0.16 select responders. Alcohol can provoke different types of liver injury. The most critical ill patients are patients suffering from severe alcoholic hepatitis (ASH) (mostly superimposed on alcoholic cirrhosis) and patients with a decompensated cirrhosis. Recently a new clinical syndrome has been described : acute-on-chronic liver failure (ACLF). GENERAL ASPECTS OF LIVER FAILURE AND PROGNOSIS There are different types of liver failure. It is important to recognize them since they all have a different prognosis and require a different therapeutic approach. Traditionally liver failure is divided in acute liver failure (ALF) which occurs suddenly in a patient without a previous liver disease and chronic liver failure due to chronic hepatic decompensation (CHD) which is found in patients with end-stage cirrhosis as a result of a slowly progression of their underlying liver disease. Since the introduction of albumin dialysis another subtype of chronic liver failure is recognized : ACLF. This is an acute and rapid deterioration within weeks of a patient with a well-compensated chronic liver disease and is clinically characterized by deep jaundice, renal impairment, hepatic encephalopathy and rapidly evolving multiorgan failure (1). In patients with alcoholic cirrhosis admitted to the hospital for a complication, ACLF has a 3 month mortality of 60 % versus 20 % in case of end-stage CHD (2) (Fig1). Spontaneous reactivation of hepatitis B presenting as ACLF in the absence of liver transplantation has a 3 month mortality of 80% illustrating the severity of this syndrome (3). The most important clinical complication in all these conditions of liver failure which directly affects outcome, is sepsis and multiorgan failure. A low threshold to start antibiotics has significantly improved the outcome of patients with ALF (4). In case of CHD sepsis occur late in the progression of the disease at the moment of severe impairment of liver function (5). In this situation prognosis at admission of the hospital is especially related to the degree of liver dysfunction and therefore MELD score is accurate to predict the mortality in this condition. In ACLF multiorgan failure occur before sepsis at an early stage of the clinical syndrome. In this regard we found in a recent prospective study that in ACLF the SOFA score was the best score to predict outcome at admission in the hospital (2). The exact pathofysiology of ACLF is still unclear. In most cases of ACLF there is a discordance between the severity of jaundice on the one hand and the degree of other features of liver impairment on the other hand. This resulted to the toxin accumulation hypothesis. Since albumin dialysis removes both water soluble and BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 99 non soluble toxins a beneficial effect in ACLF was expected and indeed an improvement in haemodynamic instability and hepatic encephalopathy was observed. (6, 7, 8) None of these devices however could improve yet overall survival. Currently an excessive pro-inflammatory response to bacterial components is thought to play an important role linking the gut, liver and systemic circulation in this syndrome (9). A crucial role in the onset of ACLF are the precipitating events. This is illustrated by the fact that early and aggressive control of these triggers allow reversal of ACLF. A common precipitating event of ACLF is variceal haemorrhage. Prophylactic use of antibiotics has significantly improved the outcome of these patients and in this regard it has been recently demonstrated that in high risk patients early control of variceal haemorrhage by TIPS prevents ACLF (10). A similar observation came recently from India. Early suppression of HBV viremia with tenofovir prevented the development of multiorgan failure in patients with spontaneous reactivation of Hepatitis B presenting as ACLF (3). The most common trigger in the Western countries of ACLF is severe alcoholic hepatitis and this will be discussed more in detail below. DIFFERENT TYPES OF LIVER FAILURE IN PATIENTS WITH ALCOHOLIC LIVER DISEASE a.Severe ASH as a trigger for ACLF One of the most important cause of chronic liver failure is alcohol. CHD is the most frequent subtype and is characterized in the initial stage by the complications of portal hypertension and mild to moderate jaundice. The one year mortality in case of the appearance of ascites is 29% and if hepatic encephalopathy occurs this is 64 % (11). The prognosis is predominantly affected by abstinence. ACLF is less frequent but in tertiary hospitals ACLF can account for more than 40 % of the emergency hospitalization due to alcoholic cirrhosis (2). In Western countries the percentage of alcoholic cirrhosis included in the studies with albumin dialysis (MARS of Prometheus) for the treatment of ACLF range from 39 to 92% (8, 12, 13). In patients with alcoholic cirrhosis ACLF can be induced by several precipitation events but the most frequent one is severe ASH, which occurred in around 25 % of our patients with ACLF (2). b.Prognostic scores used for patients with ASH Severe ASH is characterized by a rapid onset of jaundice, elevated AST (< 300 IU/ml), AST/ALT ratio > 2, bilirubin > 5 mg/dl, elevated INR and neutrophilia (14). As has been demonstrated for variceal haemorrhage and exacerbation of HBV, the best way to reverse ACLF is a rapid control of ASH in patients of which spontaneous recuperation is doubtful. Therefore prognostic scores are of importance. There are different scores which assess the severity of ASH (Table 1). There are the disease-specific prognostic models (modified Maddry’s discrimination function, the Glasgow alcoholic hepatitis score and the ABIC score) and there is the non disease-specific prognostic model: MELD. In 2 retrospective studies it was found that a MELD score of > 21 was a useful clinical tool to assess mortality of these patients (15,16). In one of the studies also a decrease in MELD by 2 points at day 7 was associated with a good prognosis. Still one of the most commonly used disease-specific score to predict outcome of ASH is the modified Maddry’s discriminant function (DF) (17). Patients with a DF < 32 have a spontaneous survival at 28 days around 90 %; if the DF is ≥ 32 the spontaneous 2 month survival is only 50 % - 65 %. These patients mostly progress to the systemic inflammatory response syndrome and multisystem organ failure which is also seen in other types of ACLF. In patients with severe ASH without contraindication (gastro-intestinal bleeding, hepatorenal syndrome, sepsis and HBV) corticosteroids seems to improve outcome. A recent meta-analysis of individual data from 5 randomized trials demonstrated that 28-day survival was higher in corticosteroid-treated patients (80% vs 66%) (18). Two disease-specific scores assessed which patients might benefit from corticosteroids: for the Maddrey score the cut-off is ≥ 32.and for the Lille score this is ≥0.45 (19). Another score which allow to select the best candidates for treatment is the Glasgow score (20). The Glasgow alcoholic hepatitis score 100 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE (GAHS) has been validated in the UK. Among patients with a DF ≥ 32 and a GAHS ≥ 9 prognosis was extremely poor if they were not treated with corticosteroids. The ABIC score identifies patients with a 90 day and 1 year survival rate of respectively 100%, 70% and 25% (21). The authors retrospectively evaluated the response to corticosteroids and found that this was 100%, 71% and 33% in the patients with low, intermediate and high risk of death respectively. For the MELD, there is uncertainly about the threshold for initiating corticosteroids. Finally one score allow to discriminate the respons rate to corticosteroids during treatment: a Lille score at day 7 of ≤ 0.16 discriminated the best responders (19). THE INTERNATIONAL LIVER CONGRESSTM 2012 101 Table 1: Prognostic scores used for patients with alcoholic hepatitis Infection is commonly seen in patients with severe ASH and is found in around 25% of the patients. Recent data demonstrated that after control of the infection corticosteroids are not contraindicated for the treatment of ASH. Infection during steroid treatment however was the explanation of non-respons to corticosteroids in agreement of the concept of the ACLF (22). c.The value of liver biopsy in patients with ASH. Although liver biopsy is not required to establish the diagnosis of ASH and a well validated histological classification is still lacking, biopsy can be helpful. Indeed as already mentioned not every sudden exacerbation of alcoholic cirrhosis is due to severe ASH (2). Biopsy will not only allow a correct diagnosis of ASH, it is helpfull to define the severity of ASH and the presence of liver polymorphonucclear infiltrate has prognostic value (23). Biopsy can also recognize the patients in a pre-cirrotic stage which might have a better outcome. Finally, biopsy can also help to diagnose sepsis in an early stage which is useful to recognize ACLF (24). CONCLUSIONS Several precipitating events can provoke ACLF in patients with alcoholic liver disease. One of the frequent triggers is severe ASH. Early and aggressive control of these precipitating events can reverse ACLF. In patients with ASH and bad prognoses corticosteroids prevents ACLF. Several disease specific prognostic scores are available for patients with ASH. Some of them are helpful to select the best candidates for corticosteroid and one score (Lille) can select non-responders early during treatment. Figure 1 Different outcome of patients with chronic liver failure due to chronic hepatitis decompensation (CHD) or acute-on-chronic liver failure (ACLF) due to alcohol (Katoonizadeh et al GUT 2010). REFERENCES Sarin SK, Kumar A, Almeida JA, Chawla YK, Fan ST, Garg H, de Silva HJ, Hamid SS, Jalan R, Komolmit P, Lau GK, Liu Q, Madan K, Mohamed R, Ning Q, Rahman S, Rastogi A, Riordan SM, Sakhuja P, Samuel D, Shah S, Sharma BC, Sharma P, Takikawa Y, Thapa BR, Wai CT, Yuen MF. Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the study of the liver (APASL). Hepatol Int. 2009;3(1):269-82. Katoonizadeh A, Laleman W, Verslype C, Wilmer A, Maleux G, Roskams T, Nevens F. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut. 2010;59(11):1561-9. Garg H, Sarin SK, Kumar M, Garg V, Sharma BC, Kumar A. Tenofovir improves the outcome in patients with spontaneous reactivation of hepatitis B presenting as acute-on- chronic liver failure. Hepatology. 2011;53(3):774-80. Rolando N, Philpott-Howard J, Williams R. Bacterial and fungal infection in acute liver failure. Semin Liver Dis. 1996;16(4):389-402. Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R. Severe sepsis in cirrhosis. Hepatology. 2009;50(6):2022-33. Evenepoel P, Laleman W, Wilmer A, Claes K, Kuypers D, Bammens B, Nevens F, Vanrenterghem Y. Prometheus versus molecular adsorbents recirculating system: comparison of efficiency in two different liver detoxification devices. Artif Organs. 2006;30(4):276-84. Laleman W, Wilmer A, Evenepoel P, Elst IV, Zeegers M, Zaman Z, Verslype C, Fevery J, Nevens F. Effect of the molecular adsorbent recirculating system and Prometheus devices on systemic haemodynamics and vasoactive agents in patients with acute-onchronic alcoholic liver failure. Crit Care. 2006;10(4):R108. Hassanein TI, Tofteng F, Brown RS Jr, McGuire B, Lynch P, Mehta R, Larsen FS, Gornbein J, Stange J, Blei AT. Randomized controlled study of extracorporeal albumin dialysis for hepatic encephalopathy in advanced cirrhosis. Hepatology. 2007;46(6):1853-62. Verbeke L, Nevens F, Laleman W. Bench-to-beside review: Acute-on-chronic liver failure linking the gut, liver and systemic circulation. Crit Care. 2011 25;15(5):233. García-Pagán JC, Caca K, Bureau C, Laleman W, Appenrodt B, Luca A, Abraldes JG, Nevens F, Vinel JP, Mössner J, Bosch J; Early TIPS (Transjugular Intrahepatic Portosystemic Shunt) Cooperative Study Group. Early use of TIPS in patients with cirrhosis and variceal bleeding. N Engl J Med. 2010;362(25):2370-9. 102 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Jepsen P, Ott P, Andersen PK, Sørensen HT, Vilstrup H. Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study. Hepatology. 2010;51(5):1675-82. Baňares R, Nevens F, Larsen FS, Jalan R, Albillos A, Dollinger M. Extracorporeal liver support with the molecular adsorbent recirculating system (MARS) in patients with acute-on-chronic liver failure The RELIEF Trial. J Heptatol. 2010;52 (Suppl 1): S459-60. Rifai K, Kribben A, Gerken G, hag S, herget-Rosenthal S, Treichel U, Betz C, Sarrazin C, Van Vlierberghe H, Hoste E, Escorsell A, Ginès P, Hafer C, Schuchmann M, Galle PR, Bernardi M, Caraceni P, Abeles D, Berr F, Knotek M, Kozik-Jaromin J, for the HELIOS Study Group. Extracorporeal liver support by fractionated plasma separation and adsorption (prometheus) in patients with acute-on-chronic liver failure (HELIOS study) : a prospective randomized controlled multicenter study. J Hepatol. 2010; 52 (Suppl. 1):S3. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360(26):2758-69. Dunn W, Jamil LH, Brown LS, Wiesner RH Kim WR, Menon KV, Malinchoc M, Kamath P, Shah V. MELD accuratelypPredicts mortality in patients with alcoholic hepatitis. Hepatology 2005;41:353-8. Srikureja W, Kyulo NL, Runyon BA, Hu Ke- Qin. MELD score is a better prognostic model than Child-Turcotte-Pugh score or discriminant function score in patients with alcoholic hepatitis. J Hepatol 2005;42:700-6. Maddrey WC, Boitnott JK, Bedine MS, Weber FL, Mezey E, White RI. Corticosteroid therapy of alcoholic hepatitis. Gastroenterology. 1978; 75:193-9 Mathurin P, O’Grady J, Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, Naveau S, Maddrey WC, Morgan TR. Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut. 2011;60(2):255-60. Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F, Hollebecque A, Serfaty L, Boleslawski E, Deltenre P, Canva V, Pruvot FR, Mathurin P. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology. 2007;45(6):1348-54. Forrest EH, Morris AJ, Stewart S, Phillips M, Oo YH, Fisher NC, Haydon G, O’Grady J, Day CP. The Glasgow alcoholic hepatitis score identifies patients who may benefit from corticosteroids. Gut. 2007;56(12):1743-6. Dominguez M, Rincón D, Abraldes JG, Miquel R, Colmenero J, Bellot P, García-Pagán JC, Fernández R, Moreno M, Bañares R, Arroyo V, Caballería J, Ginès P, Bataller R. A new scoring system for prognostic stratification of patients with alcoholic hepatitis. Am J Gastroenterol. 2008;103(11):2747-56. Louvet A, Wartel F, Castel H, Dharancy S, Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P. Infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology. 2009;137(2):541-8. Mathurin P, Duchatelle V, Ramond MJ, Degott C, Bedossa P, Erlinger S, Benhamou JP, Chaput JC, Rueff B, Poynard T. Survival and prognostic factors in patients with severe alcoholic hepatitis treated with prednisolone. Gastroenterology. 1996;110(6):1847-53. Rajiv Jalan, Rajeshwar Prosad Mookerjee. Acute-on-chronic liver failure: an early biopsy is essential? Gut. 2010; 59(11):1455-6. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 103 ALCOHOLIC STEATOHEPATITIS (ASH) Antoine Hadengue Geneva, Switzerland E-mail: [email protected] KEY POINTS • Alcoholic hepatitis is the clinical syndrome of jaundice or abnormal liver function tests in alcohol abusers. Because decompensation in ALD can result from alcoholic steato-hepatitis (ASH), infection, or other causes, ASH should be confirmed by liver biopsy. • Alcoholic steatohepatitis (ASH) is defined at liver biopsy by the coexistence of steatosis, hepatocyte ballooning and an inflammatory infiltrate with PMNs. • Alcohol abstinence is the chief, vital objective in all forms of ASH, and deserves full multidisciplinary investment. • Severe ASH at risk of early death should be identified by one of the available scoring systems before considering specific therapy. • First-line therapy in patients with severe ASH includes corticosteroids. Early non-response to steroids should be identified and stopping rules should be considered when steroids are contraindicated, for example in case of ongoing sepsis, pentoxifylline should be used. However, pentoxifyllin is not useful in combination with- or in non-responders to steroids. • N-acetylcysteine, combined to corticosteroids in patients with severe ASH, has brought survival benefit in one study and can be considered, especially in patients with poor nutritionnal status. • Renal function and infection have a major impact on survival and should be closely monitored in patients with severe ASH. • Early liver transplantation may only be considered in highly selected patients with a first episode of severe ASH, a favorable addiction profile and not responding to medical therapy. DEFINITION AND INCIDENCE The clinical syndrome of jaundice or abnormal liver function tests in alcohol abusers is called “alcoholic hepatitis”. Historically, it has also been referred to as “acute alcoholic hepatitis”. Although the clinical presentation may be abrupt, this is probably a misnomer, since alcoholic hepatitis is usually associated with extensive fibrosis or cirrhosis and often follows a protracted course, weeks after alcohol abstinence. The clinical syndrome of alcoholic hepatitis, often with ALD decompensation in non-abstinent patients, opens a differential diagnosis where alcoholic steatohepatitis (ASH) is the leading, but not the only cause. Other causes of ALD decompensation besides ASH, including infection, extensive microvesicular steatosis, or superimposed drug-induced liver injury, will not be covered here. ASH is defined at histology by the coexistence of steatosis, hepatocyte ballooning and an inflammatory infiltrate with PMNs. Uncertainty about the exact cause of the syndrome may not be an issue in non-severe forms, when no specific therapy is required. In severe forms however, where specific therapy with a potential for side-effects is considered, ASH should be confirmed by histology. Based on clinical diagnosis codes from a Danish registry the incidence of alcoholic hepatitis was estimated to range from 24 to 46 per million in women and men, respectively [1]. In the United States, a clinical diagnosis of alcoholic hepatitis accounted for 0.7 % of all hospital admissions in 2007 [2]. Because of the uncertainties behind a clinical diagnosis of “alcoholic hepatitis” and the limited number of studies with a liver biopsy to ascertain a diagnosis of ASH, the true incidence and prevalence of ASH in alcohol abusers is difficult to determine. Relying only on clinical criteria for the diagnosis of alcoholic hepatitis entails a 10-50% risk of misclassifying patients with or without ASH. This has been established in older studies [3, 4] and verified recently [5, 6]. Early liver biopsy (within 7 days) in 68 patients admitted for 104 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 105 an acute deterioration of alcoholic cirrhosis with a systemic inflammatory response (SIRS) suggestive of steatohepatitis, showed that ASH was present only in 50% [6]. Among 234 patients with a clinical suspicion of ASH, in whom particular care was taken to exclude infection, liver biopsy showed diagnoses other than ASH in 10% [5]. Based on liver biopsy in 1,604 patients admitted with alcohol abuse in France, with or without symptoms of liver disease, ASH was present in 44 % of the 411 patients with cirrhosis and 12 % of the 996 patients without cirrhosis [7]. rapidly during the course of ASH, while the healing process can be accompanied by a marked decrease in portal pressure over a few weeks. HISTOLOGICAL FEATURES OF ASH Steatohepatitis is defined by the coexistence of steatosis, hepatocyte ballooning and an inflammatory infiltrate with PMNs. These criteria are common to ASH and NASH. Similarly, the presence of Mallory’s bodies, and mega mitochondria, although not specific to alcoholic steatohepatitis, are often associated with the elementary lesions described above, both in ASH and NASH. At standard histological examination, no single criteria can differentiate ASH from NASH (which by the way was initially called “pseudo-alcoholic hepatitis”). However, lesions of steatohepatitis may appear more pronounced in patients with ASH compared with NASH. In addition, the presence of these lesions in a patient with ALD suggests active drinking. PROGNOSTIC SCORES Prognostic scores have been developed mainly to select patients with “severe” ASH, i.e. at high risk of early (1, 2, or 3 months) mortality, in order to initiate randomized trials with mortality as an end-point. CLINICAL MANIFESTATIONS AND EVALUATION When symptomatic, ASH usually presents with progressive jaundice. However, ASH should be suspected in patients with alcohol abuse presenting with any of the features of liver decompensation, such as ascites, encephalopathy or gastrointestinal bleeding. An enlarged liver is often present, which may be tender or even painful in rare cases. ASH is often be associated with SIRS, exceptionally with high fever, with or without infection. Weight loss, muscle wasting and malnutrition can be at the front scene. Besides palmar erythema and finger clubbing, spider angiomas and gynecomasty are believed to be especially prevalent when alcohol is the cause of steatohepatitis. Extrahepatic manifestations of alcohol toxicity, such as parotid gland enlargement, Dupuytren’s contracture, peripheral neuropathy or alcohol-related CNS disorders, cardiomyopathy, or history of pancreatitis may help in the diagnosis of alcohol abuse. At liver function tests, AST levels, which may be normal in asymptomatic forms, are typically elevated to 1-6 times the upper limit of the normal range. The AST/ALT ratio is usually greater than 2 which can also be seen in advanced fibrosis related to other causes of chronic liver disease [8]. Low serum albumin, a prolonged prothombin time and elevated international normalized ratio (INR) reflect the severity of liver dysfunction. Besides the possibility of leucopenia as seen in cirrhosis, neutrophilia, sometimes of high level, is a frequent feature of ASH. Imaging studies of the liver, in addition to detecting signs of advanced stages of ALD such as a dysmorphic liver, portal-systemic collaterals and splenomegaly, may evidence liver “arterialization”, related to increased resistance to portal venous blood flow and the resulting dilatation of the hepatic artery. In some cases, liver “arterialization” in ASH may translate into hypervascular, although benign, regeneration nodules. Infection is a permanent concern in patients with ASH. Active infection: In a cohort of 246 patients with severe ASH, a quarter of the patients were infected at admission, and another quarter became infected while receiving corticosteroids [9]. Even though the patient may have normal body temperature, systematic infection screening should include blood and urine cultures, ascites examination, and chest X-ray. These should be performed at admission and repeated if the clinical condition of the patient deteriorates or when an important therapeutic step is considered. Due to the high incidence of acute renal failure related to the hepatorenal syndrome (HRS) in severe ASH, repeat checks of renal function are also recommended in patients with ASH. The hepatic venous pressure gradient, measured at the time of transvenous liver biopsy, is an accurate reflection of portal pressure in ASH and carries prognostic information. Sharp portal pressure increases have been reported to reflect the severity of ASH. Clinically significant portal hypertension may emerge Caution with the use of transient elastography to estimate fibrosis is recommended in patients with a clinical diagnosis of alcoholic hepatitis. In addition to fibrosis, inflammation, cholestasis or liver congestion, and recent alcohol consumption behavior may interfere with liver stiffness measurements [10, 11]. The Maddrey Discriminant Function (MDF = bilirubin (mg/dL) + 4.6 x (patient PT - control PT)) was developed in 1978 and is still used to stratify patients into severe and non-severe forms of ASH. MDF ≥ 32 has been used in most randomized controlled trials to define “severe ASH” and demonstrate treatment efficacy in this category [12, 13]. In the absence of treatment, the 1-month spontaneous survival of patients with a DF ≥32 has fluctuated between 50 and 65 % [13, 14]. Although the most widespread and simple to interpret, MDF is limited by difficulties in standardizing prothrombin time, presence of only two categories (severe/non-severe) and lack of dynamic information to assess treatment response. The Model for End-Stage Liver Disease (MELD), widely used in liver diseases, has been evaluated to assess the severity of ASH. Although useful as a continuous measure of severity of ASH, no clearly validated cut-off point has been established that differentiates severe from non-severe ASH. In one recent retrospective report of largely untreated patients with ASH, a MELD score > 21 was associated with a 3-month mortality of 20% [15]. Although relatively easy to calculate and standardize, it has not been prospectively validated. The Glasgow Alcoholic Hepatitis Score (GAHS) [16] was also derived to assess severity of ASH in patients with suspected ASH (not all patients had biopsies). It is based on 5 laboratory values and can be calculated at day 1 or days 6-9 to give dynamic information. In patients with a MDF ≥ 32 patients and GAHS ≥ 9, 28-day survival was 52% if untreated and 78% if treated with steroids. In patients with GAHS <9 there was no difference in survival between treated and untreated groups. Although easy to calculate, the GAHS has not been validated prospectively or in biopsy-proven ASH and it is unclear whether it adds prognostic information to existing scores. The ABIC score (Age, serum Bilirubin, INR, and serum Creatinine score) has been proposed in the setting of severe ASH [17]. In patients with biopsy-proven AH, scores of < 6.71, 6.71-8.99 and ≥ 9 predicted a 90-day survival of 100%, 70% and 25% respectively. The ABIC has been studied in biopsy-proven ASH, is easy to standardise, and shows good diagnostic performance. It remains to be further validated by independent groups. The ABIC score is the only one to introduce the category of intermediate severity, in which significant mortality at long-term (i.e. at 6- or 12-month) remains a problem hitherto not addressed by most randomized trials in the field. The Lille Score is a dynamic model used to assess the treatment response at day 7 of steroid therapy (not to assess baseline severity of ASH) [18]. The Lille score takes into account markers of liver function at baseline and the bilirubin response at day 7 of corticosteroid therapy (http://www.lillemodel.com/score. asp). Six-month survival was 25% in patients with a Lille score >0.45 vs 85% in those with a Lille score < 0.45 [18]. Applying Lille score to individual patients data from 5 recent RCTs in patients with severe ASH, allowed the definition of three groups of response to corticosteroids and corresponding survival at 28 days. Complete responders, defined as Lille score <0.16, had 96% survival under steroids vs 80% without steroids (p=0.005). Partial responders, defined as a Lille score from 0.16 to 0.56, had 88% survival under steroids vs 72% without steroids (p=0.03). However, non-responders, defined as Lille score >0.56, had 50% survival under steroids, which was slightly inferior to the 56% survival in patients not receiving steroids 106 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 107 (NS). Thus, the Lille score is particularly useful to establish a stopping rule in non-responders at day 7 of steroid therapy (see below). used, is not warranted. Instead, infection screening should be systematic at admission (1 in 4 patients admitted for ASH is infected at admission) and repeated at regular intervals. TREATMENT IN ALL FORMS OF ASH Long-term management of non-alcoholic cofactors Alcohol and obesity are supra-additive factors of chronic liver disease [23]. It seems intuitive that in the long-term management of patients initially presenting with ASH, it may be relevant to pay attention to nonalcoholic cofactors of steatohepatitis, such as insulin resistance, small intestinal bacterial overgrowth, or drugs (amiodarone, tamoxifen, NSAIDs, methotrexate..). However, no trial has yet shown the value of correcting metabolic or other factors of steatohepatitis in the long-term outcome of these patients. Alcohol abstinence Alcohol abstinence improves clinical outcomes at all stages of ALD, including ASH. Therefore, abstinence should be the chief vital goal in ASH. The pursuit of abstinence deserves the full, multidisciplinary medical support, as discussed in another part of this syllabus. It should be pointed out that, except baclofen, no pharmacological therapy has been tested in the setting of ASH or decompensated cirrhosis. Specifically, disulfiram and naltrexone should be avoided in patients with ASH because of possible hepatotoxicity. Acamprosate and topiramate have not been tested in patients with cirrhosis. Of note, the only published clinical trial testing baclofen in patients with ALD [19] included a majority of decompensated, Child C patients, probably a number of whom had superimposed ASH. Withdrawal syndrome Because most patients with ASH maintain active drinking until hospital admission, systematic evaluation and management of withdrawal are mandatory in patients with ASH. We encourage the use of clinical scores, such as the revised clinical institute withdrawal assessment for alcohol scale [20] at regular intervals after admission. Specific to decompensated ALD is the risk of hepatic encephalopathy. We encourage the use of repeat doses of short-lived benzodiazepines, titrated to the alcohol withdrawal score. Malnutrition Some degree of malnutrition is nearly universal in ASH. Simple bedside methods such as the Subjective Global Assessment (SGA), or anthropometry to assess muscle wasting will identify patients at particular risk of undernutrition [21]. B-complex vitamins should be supplemented and intravenous thiamine should be administered whenever glucose infusion is used. A daily protein intake of 1.5 g/kg of body weight should be ensured, irrespective of the presence of encephalopathy. Liposoluble vitamins deficiency should be compensated. When the recommended protein-caloric intake is difficult to achieve orally, nutrition may be considered. No consistent mortality benefit with various nutritional interventions has been shown. One study comparing enteral feeding to steroids in the short-term treatment of severe ASH did not show any significant difference in 28-days mortality [22]. However, early deaths were more frequent in the group treated with TEN, while late mortality was higher in the steroid group. Since denutrition can be associated with depletion of glutathion stores, speculations on a possible synergistic effect of nutrition and steroids may be seen in light of recent data on N-acetylcysteine and corticosteroids combination [39]. Renal function Renal dysfunction is frequent during the course of severe ASH and represents an important predictor of infection and survival. The most frequent cause of acute renal failure is the hepatorenal syndrome (HRS). To best prevent the HRS, adequate volume expansion should be ensured, diuretics avoided whenever serum creatinine is not strictly normal, non-steroidal anti-inflammatory drugs and radiocontrast agents should be proscribed. Use of vasoactive drugs should be discussed early in the course of HRS, similar to HRS in other settings. Infections Bacterial infection is frequent and difficult to diagnose, since SIRS criteria are common at admission due to the inflammatory state associated with ASH. Empirical use of antibiotic administration, although widely SPECIFIC MEASURES IN SEVERE ASH Corticosteroids Starting with the seminal study by Maddrey in 1978 [12], the history of corticosteroid trials in alcoholic hepatitis looks like a long winding road. Inconsistencies may have been in part related to heterogeneity between studies and the fact that a number of patients with a clinical diagnosis of alcoholic hepatitis did not have a liver biopsy to confirm ASH. The analysis of individual data from the five most recent randomized controlled trials [4, 13, 14, 22, 24] showed that patients allocated to corticosteroid treatment had higher 28-day survival than patients allocated to non-corticosteroid treatment [25]. This result should now be acknowledged, and corticosteroids have become the first-line therapy of severe ASH. These studies also contributed to delineate the limitations to corticosteroid use in ASH : 1. The efficacy of corticosteroids is demonstrated only in patients with biopsy-proven ASH, at a dose of 40mg/day for 28 days. Steroids may be harmful in conditions other than ASH, which may represent 10-30% of patients with a clinical diagnosis of alcoholic hepatitis, dominated by infection-related decompensation of ALD. Again, when the greatest care has been taken, including systematic cultures, to rule out infection, ASH will eventually not be confirmed at liver biopsy in 10% of the patients with a clinical diagnosis of alcoholic hepatitis [5]. 2. The effect of corticosteroids on survival seems to be restricted to severe ASH, as defined by an MDF ≥ 32 [26-29]. Thus, treatment of non-severe ASH, by steroids is not warranted. 3. Only about 60 % of patients with severe forms of SAH benefit from corticosteroids. Thus, early identification of non-responders to corticosteroids (i.e. about 40% of the patients), is important to define stopping rules and limit the exposure to steroids [18]. Based on the meta-analysis of individual patient data from five RCTs of patients with a DF >32 or encephalopathy, a Lille score ≥ 0.56 at 7 days upon corticosteroids, defines non-response to steroids [18, 25]. In non-responders, not only survival at 28 days is limited to about 50%, but steroid therapy is. 4. Infection is a contraindication for corticosteroid treatment. However, this is only relevant to active, uncontrolled infection. In fact, corticosteroids may be started after infection has been controlled [9]. Pentoxifylline Pentoxifylline is an antioxidant and a weak anti-TNF agent. In patients with severe ASH (DF ≥32) treated with pentoxifylline, 6-month survival was higher than in those receiving placebo. The survival benefit was not accompanied by significant changes in liver function but related to a lower incidence of the HRS [30]. The effect of pentoxifylline on preventing the HRS was confirmed by other trials [31, Tyagi P, 2011 #1425]. 108 POSTGRADUATE COURSE SYLLABUS One study comparing pentoxifylline to corticosteroids, reported a significant prevention of the HRS, resulting in a better outcome in pentoxifylline-treated patients [32]. In a recent trial in 270 patients with severe ASH (PTX) the combination of pentoxifylline to prednisolone did not bring any benefit over corticosteroids alone. Finally, in patients with severe ASH and a poor response to corticosteroids defined by the lack of decrease in serum bilirubin, an early switch to pentoxifylline does not modify outcome [33]. Thus, in patients with severe ASH and uncontrolled sepsis representing a contraindication to steroids, pentoxyfilline can be considered as a first line therapy. However, pentoxyfilline does not seem to be useful as a rescue tool in non-responders to steroids at day 7 of therapy, with or without the HRS. Anti- TNFα agents Because strong evidence supported a central role for TNFα in experimental models of ALD, a randomized pilot study in patients with severe ASH tested single dose infliximab in combination with corticosteroids. It showed a significant improvement of liver function [34]. However, the effectiveness of anti-TNFα was not confirmed in 2 randomized controlled trials testing multiple doses of Infliximab [35] or Etanercept [36]. In fact, anti-TNFα treatment, compared to placebo, was associated with a higher probability of severe infections and deaths [35, 36]. It may be speculated that prolonged or excessive TNF blockade negatively impacts liver regeneration. N-acetylcysteine N-acetylcysteine replenishes glutathione stores in hepatocytes and can be seen as an antioxidant. Adding N-acetyl cysteine (NAC) to enteral nutrition did not bring any benefit in patients with severe ASH, possibly because glutathion stores may be restored either by TEN or by NAC [37]. N-acetylcysteine alone is inferior to corticosteroids on short-term survival [14]. In a recent trial, however, combining N-acetylcysteine with corticosteroids resulted in a lower incidence of both the HRS and infection, and in an improved 1-month survival compared to corticosteroids alone [38]. This benefit was not maintained at 6-months, raising the question of optimal duration of N-acetylcysteine administration. Liver transplantation ASH is usually considered as a contraindication for transplantation (OLT). This is related both to the fact most patients with ASH will improve for at least 6 months after abstinence has been reached, and to the “6-month abstinence rule” [39]. The 6 months’ abstinence rule, although socially acceptable and associated with low harmful alcohol relapse after OLT, can be substituted by other elements predictive of abstinence, such as social / family support and absence of psychiatric / addictive disorders [39]. New prognostic models now allow the early identification of non- or poor-responders to corticosteroids with a Lille score above 0.45 or 0.56 at day 7 of therapy and only a 25% chance of being alive at 6 months. Recently a French and Belgian group initiated an early OLT program in patients with a first episode of severe ASH not responding to medical therapy. Unequivocal improvement of survival in patients was observed in patients who received early transplantation compared both to non-random controls matched for age, sex, MDF, and Lille score, or to randomly sampled controls from a prospective database [40]. Obviously, early OLT in ASH may be relevant only in a very small minority of patients after a highly selective selection process involving patient’s families and multidisciplinary medical teams. REFERENCES BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE Sandahl TD, J.P., Thomsen KL, Vilstrup H, Incidence and mortality of alcoholic hepatitis in Denmark 1999-2008: a nationwide population based cohort study. J Hepatol, 2011. 54(4): p. 760-4. National Hospital Discharge Survey: 2007, C.f.D.C., Atlanta, USA. Kryger P, S.P., Dietrichson O, Juhl E, The accuracy of the clinical diagnosis in acute hepatitis and alcoholic liver disease. Clinical versus morphological diagnosis. Scand J Gastroenterol, 1983. 18(5): p. 691-6. Ramond MJ, P.T., Rueff B, Mathurin P, Theodore C, Chaput JC, Benhamou JP, A randomized THE INTERNATIONAL LIVER CONGRESSTM 2012 trial of prednisolone in patients with severe alcoholic hepatitis. N Engl J Med, 1992. 326: p. 507-512. Spahr, L., et al., Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis. BMC Gastroenterol, 2011. 11: p. 115. Mookerjee RP, L.C., Stauber R, Stadlbauer V, Deheragoda M, Aigelsreiter A, Jalan R, The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis. J Hepatol, 2011. 55(5): p. 1103-11. Naveau S, G.V., Borotto E, Aubert A, Capron F, Chaput JC, Excess weight risk factor for alcoholic liver disease. Hepatology, 1997. 25: p. 108-111. Nyblom H, B.U., Balldin J, Olsson R, High AST/ALT ratio may indicate advanced alcoholic liver disease rather than heavy drinking. Alcohol Alcohol, 2004. 39(4): p. 336-9. Louvet A, W.F., Castel H,Dharancy S,Hollebecque A, Canva-Delcambre V, Deltenre P, Mathurin P, Prospective screening of infection in patients with severe alcoholic hepatitis treated with steroids: early response to therapy is the key factor. Gastroenterology, 2009. 137 p. 541-548. Gelsi E, D.R., Truchi R, Marine-Barjoan E, Anty R, Autuori M, Burroni S, Vanbiervliet G, Evesque L, Cherikh F, Tran A, Effect of Detoxification on Liver Stiffness Assessed by Fibroscan((R)) in Alcoholic Patients. Alcohol Clin Exp Res, 2011. in press. Mueller S, M.G., Sarovska L, Friedrich S, Reimann FM, Pritsch M, Eisele S, Stickel F, Longerich T, Schirmacher P, Seitz HK, Increased liver stiffness in alcoholic liver disease: differentiating fibrosis from steatohepatitis. World J Gastroenterol, 2010. 16(8): p. 966-72. Maddrey WC, B.J., Bedine MS, Weber FL, Mezey E, White RI, Corticosteroid therapy of alcoholic hepatitis. Gastroenterology, 1978. 75: p. 193-9. Carithers RL Jr, H.H., Diehl AM, Shaw EW, Combes B, Fallon HJ, Maddrey WC, Methylprednisolone therapy in patients with severe alcoholic hepatitis: a randomized multicenter trial. Ann Intern Med, 1989. 110: p. 685-90. Phillips M, C.H., Portmann B, Donaldson N, Bomford A, O’Grady J Antioxidants versus corticosteroids in the treatment of severe alcoholic hepatitis--a randomised clinical trial. J Hepatol, 2006. 44 p. 784-790. Dunn W, J.L., Brown LS, Wiesner RH, Kim WR, Menon KVN, Maclinchoc M, Kamath PS, Shah V, MELD accurately predicts mortality in patients with alcoholic hepatitis. Hepatology, 2005. 41: p. 353-358. Forrest E H, E.C., Stewart S, Phillips M, Oo YH, McAvoy N C, Fisher NC, Singhal S, Brind A, Haydon G, O’Grady J, Day CP, Hayes PC, Murray LS, Morris AJ, Analysis of factors predictive of mortality in alcoholic hepatitis and derivation and validation of the Glasgow alcoholic hepatitis score. Gut, 2005. 54(8): p. 1174-1179. Dominguez M, R.D., Abraldes JG, Miquel R, Colmenero J, Bellot P, Joan-Carles Pagan G, Fernandez R, Moreno M,Banares R, Arroyo V, Caballerıa J, Gines P, Bataller R, A New Scoring System for Prognostic Stratification of Patients With Alcoholic Hepatitis. Am J Gastroenterol 2008. 103: p. 2747–2756. Louvet A, N.S., Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, Texier F, Hollebecque A, Serfaty L, Boleslawski E, Deltenre P, Canva V, Pruvot FR, Mathurin P, The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatitis treated with steroids. Hepatology, 2007. 45: p. 1348-1354. Addolorato G, L.L., Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G, Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet, 2007. 370(9603): p. 1915-1922. Sullivan, J.T., et al., Assessment of alcohol withdrawal: the revised clinical institute withdrawal assessment for alcohol scale (CIWA-Ar). Br J Addict, 1989. 84(11): p. 1353-7. Plauth, M., et al., ESPEN Guidelines on Enteral Nutrition: Liver disease. Clin Nutr, 2006. 25(2): p. 285-94. Cabre E, R.-I.P., Caballeria J, Quer JC, Sanchez-Lombrana JL, Pares A, Papo M, Planas R, 109 110 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE Gassul MA, Short- and long-term outcome of severe alcohol-induced hepatitis treated with steroids or enteral nutrition: a multicenter randomized trial. Hepatology, 2000. 32: p. 36-42. Hart, C.L., et al., Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies. BMJ, 2010. 340: p. c1240. Mendenhall CL, A.S., Garcia-Pont P, Goldberg S, Kiernan T, Seef LB, Sorrell M, Tamburro C, Weesner R, Zetterman R, Chedid A, Chen T, Rabin L, Short-term and long-term survival in patients with alcoholic hepatitis treated with oxandrolone and prednisolone. N Engl J Med, 1984. 311: p. 1464-1470. Mathurin P, O.G.J., Carithers RL, Phillips M, Louvet A, Mendenhall CL, Ramond MJ, Naveau S, Maddrey WC, Morgan TR, Corticosteroids improve short-term survival in patients with severe alcoholic hepatitis: meta-analysis of individual patient data. Gut, 2011. 60: p. 255-260. Daures JP, P.P., Bories P, Blanc P, Youfsi A, Michel H, Gremy F., Place de la corticothérapie dans le traitement des hépatites alcooliques aiguës. Résultats d’une méta-analyse. Gastroenterol Clin Biol, 1991. 15: p. 223-8. Imperiale TF, M.A., Do corticosteroids reduce mortality from alcoholic hepatitis? Ann Intern Med, 1990. 113: p. 299-307. Reynolds TB, Corticosteroid therapy of alcoholic hepatitis: how many studies it will take? Hepatology, 1990. 12: p. 619-621. Imperiale TF, O.C.J., McCullough AJ, Corticosteroids are effective in patients with severe alcoholic patients. Am J Gastroenterol, 1999. 94: p. 3066-3067. Akriviadis E, B.R., Briggs W, Han S, Reynolds T, Shakil O, Pentoxifylline improves short-term survival in severe acute alcoholic hepatitis: a double-blind, placebo-controlled trial. Gastroenterology, 2000. 119: p. 1637-1648. Lebrec D, T.D., Oberti F, Perarnau JM, Condat B, Barraud H, Saliba F, Carbonell N, Renard P, Ramond MJ, Moreau , Poynard T, Pentoxifylline does not decrease short-term mortality but does reduce complications in patients with advanced cirrhosis. Gastroenterology, 2010. 138(5): p. 1755-1762. Krishna De B, G.S., Dutta D, Baksi SD, Pani A, Ghosh P, Pentoxifylline versus prednisolone for severe alcoholic hepatitis: a randomized controlled trial. World J Gastroenterol, 2009. 15(13): p. 1613-1619. Louvet A, D.E., Dharancy S, Coevoet H, Texier F, Thévenot T, Deltenre P, Canva V, Plane C, Mathurin P, Early switch to pentoxifylline in patients with severe alcoholic hepatitis is inefficient in non-responders to corticosteroids J Hepatol 2008. 48: p. 465-470. Spahr L, R.-B.L., Pugin J, Giostra E, Frossard JL, Borisch B, Hadengue A, Rapid changes in alcoholic hepatitis histology under steroids: correlation with soluble intercellular adhesion molecule-1 in hepatic venous blood. J Hepatol, 2001. 35: p. 582-589. Naveau S, C.-M.S., Dharancy S, Mathurin P, Jouet P, Piquet MA, Davion T, Oberti F, Broët P, Emilie D, A double blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis. Hepatology, 2004. 39: p. 1390-1397. Boetticher NC, P.C., Kwo P, Abrams GA, Patel T, Aqel B, Boardman L, Gores GJ, Harmsen WS, McClain CJ, Kamath PS, Shah VH, A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis. Gastroenterology, 2008. 135(6): p. 1953-60. Moreno C, L.P., Hittelet A, Lasser L, Degre D, Evrard S, Colle I, Lemmers A, Deviere J, Le Moine O, Enteral nutrition with or without N-acetylcysteine in the treatment of severe acute alcoholic hepatitis: a randomized multicenter controlled trial. J Hepatol, 2010. 53(6): p. 1117-1122. Nguyen-Khac E, T.T., Piquet MA, Benferhat S, Goria O, Chatelain D, Tramier B, Dewaele F, Ghrib S, Rudler M, Carbonell N, Tossou H, Bental A, Bernard-Chabert B, Dupas JL, Glucocorticoids plus N-acetylcysteine in severe alcoholic hepatitis. N Engl J Med, 2011. 365(19): p. 1781-1789. Dew, M.A., et al., Meta-analysis of risk for relapse to substance use after transplantation THE INTERNATIONAL LIVER CONGRESSTM 2012 111 of the liver or other solid organs. Liver Transpl, 2008. 14(2): p. 159-72. Mathurin P, M.C., Samuel D, Dumortier J, Salleron J, Durand F, Castel H, Duhamel A, Pageaux GP, Leroy V, Dharancy S, Louvet A, Boleslawski E, Lucidi V, Gustot T, Francoz C, Letoublon C, Castaing D, Belghiti J, Donckier V, Pruvot FR, Duclos-Vallee JC, Early liver transplantation for severe alcoholic hepatitis. N Engl J Med, 2011. 365(19): p. 1790-800. Figure 1 Meta-analysis of individual patient data (n=418) from five RCTs comparing corticosteroid treatment with placebo, enteral nutrition or an antioxidant cocktail. Estimated 28-day survival according to treatment in (A) complete responders to corticosteroids (Lille score <0.16), (B) partial responders (Lille score 0.16-0.56) and (C) null responders (Lille score >0.56). From Mathurin P et al. Gut 2011 [25] with permission. 112 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE CAN WE OFFER LIVER TRANSPLANTATION TO PATIENTS WITH ALCOHOLIC HEPATITIS? ANSWER: YES Jean-Charles Duclos-Vallée Villejuif, France E-mail: [email protected] KEY POINTS • The benefits of liver transplantation (LT) in severe acute alcoholic hepatitis resistant to medical treatment have now been demonstrated. • The weakness of the 6-month abstinence rule is evidenced by the low relapse rate after LT in highly selected patients. • Before extending the indications for liver transplantation to patients with severe alcoholic hepatitis, it is necessary to define new prognostic factors for relapse and interventional therapies under a multidisciplinary approach. In Europe, alcohol is the cause of about 30% cases of end-stage liver disease and is the leading reason for liver transplantation (LT) (1). The post-LT survival rate is good, and 5-year survival is better than in patients with other indications (78% vs. 64%, p= 0.016), with an alcohol relapse rate of 15.6% (2). Alcoholic toxic liver disease (ALD) encompasses a spectrum of injuries that range from simple steatosis through severe steatohepatitis to complete progression to cirrhosis with or without alcoholic hepatitis (AH). Although patients with mild to moderate AH may respond to conservative management and abstinence, patients with severe disease (Maddrey score ≥32) have an overall mortality rate of 40% within 6 months (3). The most frequent treatment option available at present is corticosteroid therapy; if the lack of response assessed by a Lille score is greater than 0.45, then 6-month survival is lower than 25% (4). Depending on the severity of their liver disease, these patients are good candidates for liver transplantation. In patients with alcoholic cirrhosis, the benefits of LT have been demonstrated in patients with Child –Pugh class C, who have displayed a higher 1- and 5-year survival rates than their matched controls (5). Here, we shall be discussing and focusing on the major factors that justify a reassessment of our policies regarding the acceptance of liver transplantation in patients with severe acute alcoholic hepatitis. THE WEAKNESS OF THE 6-MONTH ABSTINENCE RULE – THE STRENGTH OF OTHER FACTORS Until now, alcoholic hepatitis has been considered as an absolute contraindication to liver transplantation because most transplant centres require 6 months of abstinence prior to transplantation (6). But there is now strong evidence that this 6 month abstinence rule is not scientifically relevant. The prospective study performed by DiMartini et al. showed that among patients who had been sober for 36 months, only 40% remained sober after LT (7); 36 months of pre-LT sobriety was 80% sensitive but only 40% specific in predicting post-LT abstinence. Each additional month of pre-LT sobriety reduced the risk of drinking postLT by 33%. However, the authors could not identify a specific length of pre-LT sobriety that could predict abstinence (7). They emphasised the fact that other factors such as alcohol dependence, family history, depressive disorders and social support (i.e. marital status) should be evaluated and taken into account because of their influence on patient and graft survival (8). Moreover, during a retrospective study on long-term follow-up, patients who relapsed back into harmful drinking had poorer survival when compared to abstainers (45% vs. 86%, p< 0.05) (9). Different trajectories of depressive symptoms can predict longterm survival after LT. In a recent prospective study analyzing different trajectories of alcohol use, 113 BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 113 of 208 patients (54%) had no reported alcohol use post-LT using any measure (10). Among the 95 nonabstainers, four distinct trajectories of alcohol consumption could be identified. The majority (n=55) drank small quantities infrequently, but three other groups also emerged; early onset moderate use that diminished over time (n=13), later onset moderate use that increased over time (n=15, group 4) and an early onset, heavy and increasing pattern of use (n=12, group 5). In terms of the comparative outcome between these groups, deaths due to recurrent alcoholic liver disease, steatohepatitis or rejection were more frequent in groups 3 and 5. CURRENT EXPERIENCE OF LIVER TRANSPLANTATION FOR SEVERE ACUTE ALCOHOLIC HEPATITIS Few data are available concerning retrospective studies which have analysed the influence of acute alcoholic hepatitis on survival following liver transplantation. In the study by Tomé et al. on patients transplanted for alcoholic cirrhosis, survival was similar in patients with superimposed alcoholic hepatitis and with liver cirrhosis alone (n=32) (11). Moreover, there was no difference in survival between patients with mild and severe alcoholic hepatitis. In the study by Wells (12), histologically acute alcoholic hepatitis in the explanted recipient liver did not predict a poorer outcome in terms of relapse, allograft survival or patient survival among liver transplant recipients (12). We recently reported our French experience from seven centres (13) in a study that included 26 patients with severe alcoholic hepatitis with at a high risk of fatality because of a Median Lille score of 0.88. These patients were carefully selected: all had good social support, no prior episodes of known alcoholic liver disease and no evidence of severe psychological disorders. This selection represented fewer than 2% of patients admitted for an episode of severe alcoholic hepatitis. Survival was excellent, with 6-month survival and 24-month survival rates of 77 % and 71%, respectively. The 6-month survival rate was significantly higher than among matched controls, in whom 6-month survival was 23%. Despite counselling with an addiction specialist, three patients restarted their alcohol consumption during the post-LT period: one at 720 days, one at 740 days and one at 1140 days post-LT. Two of these patients remained daily consumers (30 g per day and >50 g per day), whereas one only drank occasionally (approximately 10 g per week). However, none of them experienced graft dysfunction. This highlighted the somewhat arbitrary nature of the 6-month rule of abstinence. But we should of course bear in mind that these patients were highly selected. Because there may have been bias in the selection of candidates, we must now take the opportunity to define new prognostic factors for a relapse of alcohol consumption after LT for severe acute alcoholic hepatitis. In the same way, it is necessary to define any clear patterns in the evolution of alcohol consumption that might emerge following LT. A RETHINK OF OUR APPROACH TO TRANSPLANTATION FOR ALCOHOLIC LIVER DISEASE: OBJECTIVES FOR THE NEAR FUTURE; AN ETHICAL POINT OF VIEW The approval of liver transplantation for severe acute alcoholic hepatitis in selected patients is an important step towards accepting that addiction is a chronic, relapsing disease of the brain (14). Once this situation has been accepted, and new prognostic markers have been developed, we will be able to define new protocol strategies for severe liver disease in alcoholic patients. In this context, it is crucial to include geneenvironment interactions in order to unravel the aetiological factors underlying alcohol outcomes before and after LT (15). In a recent study, it was shown that gene polymorphism of Val66Met Brain-Derived 114 POSTGRADUATE COURSE SYLLABUS Neurotrophic Factor (BDNF) (a neurotrophin involved in the development and survival of neurons and in modulating the activity of neurotransmitter systems) was associated with a higher risk and earlier occurrence of relapse among patients treated for alcohol dependence (16). Future research should therefore involve multiple assessment points prior to the time of relapse which should help to identify potential mediators by which genetics can impact vulnerability to relapse. In conclusion, it is necessary to achieve a precise and uncontroversial definition of alcoholic disease, particularly in the context of acute alcoholic hepatitis. One ethical standpoint might be to promote debate between neuroscientists, hepatologists, addictologists, philosophers and sociologists in order to establish rules for government policies in a context of organ shortages (17). At the same time, these findings will help to develop new targets for preventive and interventional treatment resources for these particular individuals at specific risk time points. REFERENCES BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE Burra P, Senzolo M, Adam R, Delvart V, Karam V, Germani G, Neuberger J. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am J Transplant;10:138-148. Hartl J, Scherer MN, Loss M, Schnitzbauer A, Farkas S, Baier L, Szecsey A, et al. Strong predictors for alcohol recidivism after liver transplantation: non-acceptance of the alcohol problem and abstinence of <3 months. Scand J Gastroenterol;46:1257-1266. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med 2009;360:2758-2769. Louvet A, Naveau S, Abdelnour M, Ramond MJ, Diaz E, Fartoux L, Dharancy S, et al. The Lille model: a new tool for therapeutic strategy in patients with severe alcoholic hepatiti treated with steroids. Hepatology 2007;45:1348-1354. Poynard T, Naveau S, Doffoel M, Boudjema K, Vanlemmens C, Mantion G, Messner M, et al. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999;30:1130-1137. Lucey MR, Brown KA, Everson GT, Fung JJ, Gish R, Keeffe EB, Kneteman NM, et al. Minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the American Society of Transplant Physicians and the American Association for the Study of Liver Diseases. Liver Transpl Surg 1997;3:628-637. DiMartini A, Day N, Dew MA, Javed L, Fitzgerald MG, Jain A, Fung JJ, et al. Alcohol consumption patterns and predictors of use following liver transplantation for alcoholic liver disease. Liver Transpl 2006;12:813-820. Pageaux GP, Bismuth M, Perney P, Costes V, Jaber S, Possoz P, Fabre JM, et al. Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter? J Hepatol 2003;38:629-634. Pfitzmann R, Schwenzer J, Rayes N, Seehofer D, Neuhaus R, Nussler NC. Long-term survival and predictors of relapse after orthotopic liver transplantation for alcoholic liver disease. Liver Transpl 2007;13:197-205. DiMartini A, Dew MA, Chaiffetz D, Fitzgerald MG, Devera ME, Fontes P. Early trajectories of depressive symptoms after liver transplantation for alcoholic liver disease predicts long-term survival. Am J Transplant;11:1287-1295. Tome S, Martinez-Rey C, Gonzalez-Quintela A, Gude F, Brage A, Otero E, Abdulkader I, et al. Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease. J Hepatol 2002;36:793-798. Wells JT, Said A, Agni R, Tome S, Hughes S, Dureja P, Lucey MR. The impact of acute alcoholic hepatitis in the explanted recipient liver on outcome after liver transplantation. Liver Transpl 2007;13:1728-1735. THE INTERNATIONAL LIVER CONGRESSTM 2012 115 Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, Castel H, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med;365:1790-1800. Leshner AI. Addiction is a brain disease, and it matters. Science 1997;278:45-47. van der Zwaluw CS, Engels RC. Gene-environment interactions and alcohol use and dependence: current status and future challenges. Addiction 2009;104:907-914. Wojnar M, Brower KJ, Strobbe S, Ilgen M, Matsumoto H, Nowosad I, Sliwerska E, et al. Association between Val66Met brain-derived neurotrophic factor (BDNF) gene polymorphism and post-treatment relapse in alcohol dependence. Alcohol Clin Exp Res 2009;33:693-702. Perring C. Bridging the Gap between Philosophers of Mind and Brain Researchers: The Example of Addiction. Mens Sana Monogr;9:193-201. 116 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE CAN WE OFFER LIVER TRANSPLANTATION TO PATIENTS WITH ALCOHOLIC HEPATITIS? ANSWER: NO James Neuberger Bristol, UK E-mail: [email protected] The arguments against the use of livers from deceased donors are summarised below. These arguments do not express the opinions of the author, the Queen Elizabeth Hospital or NHS Blood and Transplant. KEY POINTS • Access to liver transplantation should be based on the transparent criteria of need, benefit, justice and equity. Those with alcoholic hepatitis (AH) have the same right to be considered for liver transplantation (LT) as all other patients on the same non-judgemental criteria and without a need for a fixed, arbitrary period of abstinence. • While the landmark study from Mathurin shows that transplantation can be done successfully for highly selected patients with AH, outcomes after transplantation are less good than for other indications and a significant proportion of those who met the criteria for transplantation will survive without surgery. These are spared the long-term consequences of immunosuppression and its associated risks of cancer, infection and kidney failure. • These observations suggest that transplantation for AH is not an efficient use of scarce resources and will deprive those patients who will have a better outcome. • Newer therapies for AH may prove more effective and safer than LT. • Because there is a shortage of donor livers, clinicians will need to identify those who would therefore lose access to transplantation if the recipient pool is increased. • Public opinion is against the use of donated livers for those with alcohol-associated liver disease so widespread use of donated livers may result in a decrease in donations. INTRODUCTION The number of people who would benefit from liver transplantation is considerably greater than the number of available grafts donated after death. Therefore this scarce resource needs to be rationed. While livers can be allocated using a number of different approaches (such as need, benefit or utility), it is also essential that donated livers are allocated according to a process that is objective, transparent and just. Although allocation models vary between jurisdictions, all models include elements of benefit and need. Allocation of donated livers to those with end-stage liver disease from self-induced habits has long attracted controversy but it is not the role of the clinician to make value judgements. Allocation of organs to those with self-induced liver damage (whether from alcohol, drug use or excessive eating) should be based on need and benefit, as for any other indication. In those with alcohol-associated liver disease, whether with cirrhosis or acute alcoholic hepatitis, allocation should be based on: • Need: will the patient die from liver failure in the absence of transplantation • Benefit: will the patient have sufficient benefit from the transplant • Outcome: will the patient comply with the need for follow-up and monitoring and avoid alcohol excess BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 117 NEED AND BENEFIT Does the patient need a transplant? In many ways the patient with AH should be considered in the same way as the patient with fulminant hepatic failure (FHF): if the patient survives the initial illness, then survival is likely to be very good and similar to the normal healthy population, if abstinence is maintained (Sandahl (a)). This contrasts with the patient with cirrhosis where there is a progressive risk of decompensation, liver cell cancer and death. Life after transplantation, while usually very good, is not normal in either quality or quantity. Those who survive the first year have an increased risk of death compared with the age matched population. For example, UK figures show that a male aged 45 years at transplantation who survives the first post operative year had a survival reduced by 17 years which represents a 15 year loss of life expectancy. There is an increased risk of malignancy (at least 2-fold compared with aged and sex matched population), a 2-3 fold increased risk of death from cerebrovascular and cardiovascular disease, as well as infection and renal failure. Indeed, in the long term, the risk of renal failure is likely to be even greater in those grafted for AH since renal impairment is common and pre-transplant renal impairment is good prognostic marker for late stage renal failure post LT. The quality of life is also reduced with only half returning to work or home-making. Is a period of abstinence necessary? In many patients with alcoholic liver disease, abstinence is associated with improvement. Often a period of abstinence is required, not only to assess whether the patient will improve to such an extent that transplantation is not required but also to explore why the patient has drunk excessively and to put in place support so the patient will be helped to maintain abstinence. There is little place for a fixed period of abstinence as there are few data to justify any given period (Brown) and in those with severe disease, such as AH, death may be the price of proving abstinence. In the UK, there is no requirement for a fixed period. Will the patient return to alcohol? Despite much public concern, the evidence suggests that a return to a damaging pattern of alcohol consumption is low: indeed, our own data show that, at 5 years, graft loss from alcohol is similar to that from recurrent PBC (4%) and considerably less than for HCV infection (25%). Nonetheless, a patient returning to alcohol does have a major adverse impact on public perception. Will the patient survive without a transplant While there are several prognostic models that predict survival of those with AH, these models are relatively imprecise when applied to the individual (Sandahl (b), Singal). Thus, there is a real risk that transplantation will be done needlessly and another recipient dies. Are there other potentially less toxic treatments There is an increasing number of agents being assessed for those with AH: these include corticosteroids, anti-TNF, N-acetyl cysteine, oxypentifylline as well as new potential targets such as CXC chemokines, and osteopontin (Gao, Altamirano). If effective, the patient is more likely to return to a better quality and quantity of life than with a transplant. BENEFIT There have been several case reports showing that liver transplant can be done successfully in alcoholic hepatitis (Singhal) but the landmark study by Mathurin and colleagues provides the first clear evidence that there is a survival benefit. While this study shows clearly that transplantation can be offered with survival benefit to a highly selected group of patients with AH, it does not mean that this scarce resource should be allocated to this group. Survival of the transplanted group is less than would be expected in those with cirrhosis or acute liver failure: current European and US data suggest that survival rates of over 90% should be anticipated at 1 118 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE THE INTERNATIONAL LIVER CONGRESSTM 2012 119 NOTES year (Dawwas et al) and over 70% at 5 years, whether done for cirrhosis (alcohol-associated and other etiologies) or acute liver failure. Survival of the control group is not that poor: Mathurin’s study showed that those who meet the criteria for transplantation but are not transplanted will have more than 25% probability of being alive at 12 months. Thus the overall benefit of transplantation in those with AH is less than for accepted indications (including alcohol-associated cirrhosis). If transplantation is accepted for AH, where the absolute and relative benefit is less than for other indications, then surely similar considerations must apply to those with primary liver cell cancers outwith the UCSF criteria or those with changiocarcinoma who are excluded from access to transplantation, not because they would not benefit but because they would not benefit enough. PUBLIC ATTITUDES Although allocation should be done on legally and ethically valid grounds, it must be recognised that where ever public opinion has been sought, the public would give very low priority to those who provide not only the funds for transplantation but also the grafts (ref). For the public to lose confidence in the process of patient selection and organ allocation will jeopardise an already fragile availability. This may be exacerbated when, in those jurisdictions where donated livers are allocated according to MELD score, those with AH would have priority. WHO DOES NOT GET A TRANSPLANT? Finally, the organ donor pool is already inadequate for the need; if the recipient pool is to be expanded by inclusion of new indications, then others must be denied access. Those who advocate transplanting carefully selected patients with AH must agree who to exclude, unless the donor pool is expanded. The study from Mathurin suggests that less than 3% of the donor pool would be taken by those with AH: it is a concern that if transplantation were used for those selected patients with AH, the strict criteria used by Mathurin and colleagues would be gradually eroded and more patients would be offered and receive access to this scarce resource. REFERENCES Altamirano J, Bataller R. Alcoholic liver disease: pathogenesis and new targets for therapy. Nat Rev Gastroenterol Hepatol 2011;8:491-501. Brown RS, Transplantation for alcoholic hepatitis – time to re-think the 6-month rule. New Engl J Med 2011;365:1836-8. Dawwas MF, Gimson AE, Lewsey JD, Copley LP, van der Meulen JHP on behalf of the UK and Ireland Liver Transplant Audit, Survival after liver transplantation in the United Kingdom and Ireland compared with the United States. Gut 2007;56:1606-13. Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets, Gastroenterology 2011;141:1572-85. **Mathurin P, Moreno C, Samuel D et al. Early liver transplantation for severe alcoholic hepatitis. New England J Med 2011;365:1790-1800. Sandahl TD, Jepsen P, Thompsen KL, Vilstrup H. Incidence and mortality of alcoholic hepatitis in Denmark 199802998: a nationwide population based cohort study. J Hepatol 2011;54:760-4. Sandahl TD, Jepsen P, Ott P, Vilstrup H. Validation of prognostic scores for clinical use in patients with alcoholic hepatitis. Scan J Gastroenterol 2011;46:1127-32. (b) Singal AK, Duchini A. Liver transplantation in acute alcoholic hepatitis: current status and future development. World Journal of Hepatology 2011;3:215-8. CLINICAL CASE: LONG-TERM MANAGEMENT OF ALD A. De Gottardi Bern, Switzerland N. Goossens Geneva, Switzerland E-mail: [email protected] A 48 year old man with chronic HCV infection, genotype 1b and cirrhosis (Child-Pugh B 7, MELD 14) comes for a routine visit to your outpatient clinic. He was treated for alcoholic hepatitis 5 years ago and after this episode he continued to drink excessively. After an inpatient treatment for alcoholism, he stopped his alcohol intake 6 months ago. Currently he drinks 3 alcohol-free beers a day. He injected intravenous drugs when he was a teenager and he currently consumes intranasal cocaine once a month. He smokes 20 cigarettes per day. His medication includes losartan, sertralin, propranolol, spironolactone and torasemide. He works as a barkeeper and has a stable family situation. An ultrasound examination with intravenous contrast shows a 3 cm lesion in the right liver with arterial enhancement and washout suggesting hepatocellular carcinoma. There is, in addition, a partial thrombosis of the splenomesenteric confluence. There is no ascites and the spleen is 15 cm in diameter. Laboratory analyses show albumin 31 g/L, bilirubin 32 umol/L (1.87 mg/dL), creatinine 101 umol/L (1.14 mg/dL), INR 1.5, alpha-fetoprotein 20 ug/L. 120 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 121 NOTES CLINICAL CASE: LONG-TERM MANAGEMENT OF ALD A. De Gottardi Bern, Switzerland N. Goossens Geneva, Switzerland E-mail: [email protected] A 48 year old man with chronic HCV infection, genotype 1b and cirrhosis (Child-Pugh B 7, MELD 14) comes for a routine visit to your outpatient clinic. He was treated for alcoholic hepatitis 5 years ago and after this episode he continued to drink excessively. After an inpatient treatment for alcoholism, he stopped his alcohol intake 6 months ago. Currently he drinks 3 alcohol-free beers a day. He injected intravenous drugs when he was a teenager and he currently consumes intranasal cocaine once a month. He smokes 20 cigarettes per day. His medication includes losartan, sertralin, propranolol, spironolactone and torasemide. He works as a barkeeper and has a stable family situation. An ultrasound examination with intravenous contrast shows a 3 cm lesion in the right liver with arterial enhancement and washout suggesting hepatocellular carcinoma. There is, in addition, a partial thrombosis of the splenomesenteric confluence. There is no ascites and the spleen is 15 cm in diameter. Laboratory analyses show albumin 31 g/L, bilirubin 32 umol/L (1.87 mg/dL), creatinine 101 umol/L (1.14 mg/dL), INR 1.5, alpha-fetoprotein 20 ug/L. ALCOHOL CONSUMPTION AS A CO-FACTOR FOR OTHER LIVER DISEASES Helmut K. Seitz Heidelberg, Germany E-mail: [email protected] KEY POINTS • Chronic alcohol consumption is a risk factor the deterioration of various types of liver diseases, such as hepatitis B and C, NAFLD, hereditary haemochromatosis and drugs induced liver injuries including vitamin E associated liver fibrosis. • Depending on the underlying liver disease this negative effect of alcohol is time and dose dependent but may occur already at much lower alcohol intake as compared to an alcohol dose necessary to initiate alcoholic liver disease itself. • Alcohol intake should be avoided or at least limited and ... not consumed chronically under these conditions. INTRODUCTION Chronic alcohol consumption is a major risk factor for chronic liver disease. Beside the fact that alcohol by itself causes chronic liver disease an additional consumption of alcohol in the presence of other types of liver diseases may result in a progression of the disease. According to the data of the Centre of Disease Control and Prevention in 2007 24 % of all chronic liver diseases are due to alcohol, 14 % to alcohol and hepatitis C and 3 % to alcohol and hepatitis B (1). In addition, alcohol may also negatively influence the course of non-alcoholic fatty liver disease (NAFLD) (2) and of hereditary hemochromatosis (HH) (3). Finally, alcohol interacts with the metabolism of certain drugs (4) and vitamin A (5) resulting occasionally in an increased toxicity of these compounds. ALCOHOL AND HEPATITIS C Influence of alcohol of the prevalence of HCV infection It has been shown that the prevalence of hepatitis C virus (HCV) infection increases with the progression of alcoholic liver disease (ALD) (Fig.1). This increase in hepatitis C infection in alcoholics may be due to a risky life style of these patients often associated with drug abuse as well as to the immunosuppressive action of alcohol. Hepatic interaction of alcohol and HCV virus reduplication, fibrosis and hepatocellular carcinoma (HCC) The impact of alcohol consumption on serum HCV RNA levels shows clearly that with increasing self reported alcohol consumption serum HCV RNA increases constantly (6) (Fig.2). On the other hand it has been shown that serum HCV RNA decreases with alcohol reduction (Fig.3). In this study by Cromie and coworkers (7), serum HCV RNA copies dropped significantly (p = 0.018) 4 months after alcohol consumption was reduced. Alcohol consumption also resulted in progression of hepatitis C (8). A great number of studies have shown that chronic alcohol consumption mostly of more than 50 grams alcohol per day significantly leads to disease progression (Tabl.1, Fig.4). Fibrogenesis was also found to be faster under alcohol consumption as compared to non drinking (Fig.5) (9). In a study by Poynard et al., patients with more than 50 grams alcohol per day had an increased fibrosis score regardless of the age at biopsy and regardless of the duration of infection (10). Also small amounts of daily alcohol consumption on the course of hepatitis C have been investigated. 78 patients with two liver biopsies, 6.3 years from each other and an alcohol consumption of less than 40 grams per day (median 5 g/day, 1 - 12 g/day) have been studied (11). The results showed an increasing progressive fibrosis with an increased total alcohol intake (15.4 kg vs. 3.9 kg; p = 0.007) with an increased daily alcohol consumption (5.7 g/day vs. 2.6 g/day; p = 0.03) and a higher drinking frequency (35 vs. 8 days/year; p = 0.006). 122 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Chronic alcohol consumption in hepatitis C not only stimulates fibrogenesis but also hepatocarcinogenesis demonstrated by a number of studies. In the study by Tagger and co-workers from Italy (12) alcohol of more than 80 grams per day increased the risk for HCC significantly by a factor of 7.3 when compared to less than 40 grams. In hepatitis C patients this risk increased to 126. It also should be noted that hepatitis C patients with less than 40 grams ethanol per day showed an increased risk for HCC with an odds ratio of 26 as compared to non-alcohol consumers. Additional results were obtained from Hassan and co-workers from the US (13). In this study, it has been shown that those patients with hepatitis C who consume alcohol had a relative risk of 54 as compare to 19 in those who abstained from alcohol. IN SUMMARY 1. 2. 3. 4. Fibrogenesis is dose independent and starts already at small alcohol doses (below 30 g/day). There is no safe alcohol dose in patients with HCV infection. It has to be emphasized that patients with overweight and obesity as well as diabetics are especially on risk. HCV patients with excessive alcohol abuse have a 2 to 3 fold increased risk to develop a severe liver disease compared with HCV patients without any alcohol history. It is still unclear how long a patient has to be alcohol abstinent until a negative effect of alcohol disappears. Alcoholics with a HCV infection are easier to motivate for abstinence as compared to alcoholics without HCV infection. Effect of alcohol on the response to HCV therapy Alcoholics have a poorer response rate to interferon therapy. The question appears whether this is an inhibitory effect of alcohol or non-compliance. It has to be emphasized that there was an increased rate of non-compliance in 726 patients with alcohol consumption during the last 10 months of therapy. When noncompliance was considered respond rates between patients with and without alcohol consumption where found to be comparable (14). Therefore, it has been concluded that compliance in alcoholics is probably the major cause for a poor response to HCV therapy. Possible mechanisms of the synergism of alcohol and HCV Various mechanisms of alcohol-HCV-interaction have been discussed: 1. Stimulation of HCV replication by alcohol 2. Increased occurrence of quasispecies 3. Increased apoptosis 4. Immunosuppression by ethanol 5. Additional Oxidative stress due to ethanol (Induction of cytochrome P-4502E1) 6. Stimulation of hepatic steatosis by ethanol HEPATITIS B AND ALCOHOL In contrast to hepatitis C, the data for the interaction of ethanol with hepatitis B is limited. Unquestionable alcohol accelerates carcinogenesis in patients with hepatitis B infection. In a Japanese study it has been shown that patients with hepatitis B infection develop HCC proximately ten years earlier than those patients who did not drink at all. This occurred already at an alcohol dose less than 24 grams per day and did further increase with advancing alcohol doses (15). ALCOHOL AND NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) Although it has been reported in epidemiologic studies that small amounts of alcohol may improve peripheral insulin resistance which in many cases occurs in NAFLD (16), it also has been shown that additional alcohol intake deteriorate NAFLD at various states of the disease in animals (2) as well as in humans (17-20). In the Northern Italy Dionysos-Study it has been shown that alcohol consumption of more than 60 grams per day increased fatty liver diagnosed by ultrasound by 46 % as compared to 16 % in control Individuals. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 123 Individuals with a body mass index of more than 25 kg per m2 have a further increase in steatosis to more than 70 % and if both overweight and alcohol consumption comes together fatty liver occurred in more than 90 % (17). Hepatic fibrosis also increases with alcohol consumption. A French study showed that daily alcohol intake of more than 100 grams showed almost a double increased risk for cirrhosis of the liver in patients with a body mass index of 29 as compared to those with 21 (Fig.5)(18,19). It has been shown recently by a retrospective epidemiologic study that even social drinking in patients with NASH resulted in a significant increased risk for HCC (Fig6) (20). Animal studies have clearly demonstrated that ethanol administration deteriorates fatty liver disease induced by high fat diets and may also enhance the generation of carcinogenic DNA lesions (2,21) HEREDITARY HAEMOCHROMATOSIS (HH) AND ALCOHOL According to the data from the National Health and Nutrition Examination Survey (NHANES 1) iron overload is a negative prognostic factor for the development of liver disease (3). More than two drinks per day had a hazard ratio of 4.1 for liver disease, while two drinks per day plus a transferin saturation of more than 40 % had a hazard ratio of 6.9. This is not surprising as hepatic iron is toxic. Alcohol increases reactive oxygen species by producing H2O2 which may lead to increased iron absorption and iron release due to a decrease in hepcidin. This may also lead to an increased iron accumulation in the liver with increased toxicity (Fig.7). Thus, individuals with HH should avoid alcohol consumption. ALCOHOL AND DRUG INTERACTION Toxicity of various drugs may be increased by concomitant alcohol consumption. This is especially wellknown for methotrexate. Chronic methotrexate administration in higher dosis may result in stellate cell activation leading to centrizonal fibrosis which is further enhanced by alcohol consumption, since alcohol by itself leads to an activation of stellate cells. As a result central portal fibrosis occurs (Fig.8). In addition alcohol induces cytochrome P450 2E. Beside the fact that CYP2E1 is responsible for ethanol metabolism, it is also responsible for the metabolism of various drugs, procarcinogens and xenobiotics (4) (Fig.9). In this context two drugs are special importance, namely paracetamol (acetaminophen) (4) and isoniazide (22). An induction of CYP2E1 by alcohol results in an enhanced metabolism of paracetamol with an increased generation of highly toxic intermediates which are usually detoxified by glutathione to become non-toxic. Since alcohol decreases hepatic glutathione levels, this detoxification pathway cannot occur and highly toxic intermediates bind to hepatocytes and induce severe hepatic injuries (Fig.10). Another interaction occurs with isoniazide, a tuberculostatic drug (22). This is also of importance since alcoholics have an increased risk for tuberculosis. Isoniazide toxicity depends on two factors: 1. The speed of isoniazide acetylation. 2. The speed of the metabolism of the intermediate acetylhydrazine by CYP2E1 (Fig.11). If isoniazide is acetylated adequately, acetylisoniazide, acetyl hydrazin and finally the detoxification product diacetylhydrazin occurs. However, in a slow metabolizer the intermediate acetylhydazine accumulates and may be further metabolized by CYP2E1. CYP2E1 is polymorph coding for a rapid or a slow metabolizing protein. If the individual is a rapid CYP2E1 metabolizer and a slow acetylizer, hepatotoxins may occur and may injure the liver (Fig.12). Other drugs, chemicals and carcinogens interactions with alcohol are shown in table 2. Finally, it should be pointed out that vitamin A and beta carotene taking in access may lead to hepatic fibrosis and cirrhosis. Additional alcohol stimulates the development of hepatic cirrhosis by CYP2E1 mediated increase in the metabolism of retinol and retinoic acid (5). As retinoic acid decreases 1. an increase in the expression of the AP1 gene occurs leading to hyperproliferation, a procarcinogenic state (23) and 2. Various apoptotic intermediates are generated damaging the liver (24) (Fig.13). Thus, vitamin A and alcohol should not be taken together. 124 POSTGRADUATE COURSE SYLLABUS REFERENCES: BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE Singal AK, Anand BS Mechanisms of synergy between alcohol and hepatitis C virus J Clin Gastroenterol 2007;41:761-72. Wang Y, Seitz H, Wang X. Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats. Alcoholism: Clinical and Experimental Research 2010; 34:567-73. Ioannou GN, Weiss NS, Kowdley KV. Relationship between transferrin-iron saturation, alcohol consumption, and the incidence of cirrhosis and liver cancer. Clin Gastroenterol Hepatol 2007;5:624-9. Seitz HK, Mueller S. Alcohol metabolism and its consequences. In in press Wang XD, Seitz HK. Alcohol and retinois interaction. In: Watson RR, Preedy VR (eds) Nutrition and Alcohol:Linking nutrient interactions and dietary intake. CRC Press Boca Raton, London, New York, Washington. Pp 313-21. Pessione F, Degos F, Marcellin P, Duchatelle V, Njapoum C, Martinot-Peignoux M, Degott C, Valla D, Erlinger S, Rueff B. Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology. 1998;27:1717–1722. Cromie SL, Jenkins PJ, Bowden DS, Dudley FJ. Chronic hepatitis C: effect of alcohol on hepatitic activity and viral titre. J Hepatol. 1996;25:821–826. Mueller S, Millonig G, Seitz HK. Alcoholic liver disease and hepatitis C: a frequently underestimated combination. World J Gastroenterol 2009;15:3462-71 Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ. Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology. 1998;28:805–809. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet. 1997;349:825–832. Westin J, Lagging M, Spak F, Aires N, Svensson E, Lindh M, Dhillon AP, Norkrans G, Wejstal R. Moderate alcohol intake increases fibrosis progession in untreated patients with hepatitis C virus infection J Virol Hepat 2002;9:235-41. Tagger A, Donato F, Ribero ML, Chiesa R, Portera G, Gelatti U, Albertini A, Fasola M, Boffetta P, Nardi G. Case-control study on hepatitis C virus (HCV) as a risk factor for hepatocellular carcinoma: the role of HCV genotypes and the synergism with hepatitis B virus and alcohol. Brescia HCC Study. Int J Cancer 1999;81:695-9. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL, Beasley P, Patt YZ. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 2002;36:1206-13. Anand BS, Currie S, Dieperink E, Bini EJ, Shen H, Ho SB, Wright T, VA-HCV-001 Study Group. Alcohol use and treatment of hepatitis C virus: results of a national multicenter study. Gastroenetrology 2006;130:1607-16. Ohnishi K, Iida S, Iwama S, Goto N, Nomura F, Takashi M, Mishima A, Kono K, Kimura K, Musha H, Kotota K, Okuda K. The effect of chronic habitual alcohol intake on the development of liver cirrhosis and hepatocellular carcinoma: relation to hepatitis B surface antigen carriage. Cancer 1982;49:672-7 Greenfield JR, Samaras K, Hayward CS, Chisholm DJ, Campbell LV. Beneficial postprandial effect of a small amount of alcohol on diabetes and cardiovascular risk factors: modification by insulin resistance. J Clin Endocrin Metab 2005;90:661-72. Bellentani S, Tiribelli C. The spectrum of liver disease in the general population: lesson from the Dionysos study. J Hepatol 2001; 35:531-7. Naveau S, Giraud V, Borotto E, Aubert A, Capron F, Chaput JC. Excess weight risk factor for alcoholic liver disease. Hepatology 1997;25:108-11. Raynard B, Balian A, Fallik D, Capron F, Bedossa P, Chaput JC, Naveau S. Risk factors of THE INTERNATIONAL LIVER CONGRESSTM 2012 125 fibrosis in alcohol-induced liver disease. Hepatology 2002;35:635-8 Ascha MS, Hanouneh IA, Lopez R, Tamimi TA, Feldstein AF, Zein NN. The incidence and risk factors of hepatocellular carcinoma in patients with nonalcoholic steatohepatitis. Hepatology 2010;51:1972-8. Wang Y, Millonig G, Nair J, Patsenker E, Stickel F, Mueller S, Bartsch H, Seitz HK. Ethanol-induced cytochrome P4502E1 causes carcinogenic etheno-DNA lesions in alcoholic liver disease. Hepatology 2009;50:453-61. Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD. Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003;37:924-30 Wang XD, Liu C, Chung J, Stickel F, Seitz HK, Russell RM. Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver. Hepatology 1998;28:744-50. Dan Z, Popov Y, Patsenker E, Preimel D, Liu C, Wang XD, Seitz HK, Schuppan D, Stickel F. Hepatotoxicity of alcohol-induced polar retinol metabolites involves apoptosis via loss of mitochondrial membrane potential. FASEB J 2005;19:845-7. Figure 1 126 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 Figure 2 Figure 5 Figure 3 Figure 6 Figure 4 Figure 7 THE INTERNATIONAL LIVER CONGRESSTM 2012 127 128 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 Figure 8 Figure 11 Figure 9 Figure 12 Figure 10 Figure 13 THE INTERNATIONAL LIVER CONGRESSTM 2012 129 130 Table 1 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 131 HEPATOCELLULAR CARCINOMA: IS IT DIFFERENT IN PATIENTS WITH ALCOHOLIC LIVER DISEASE? Thomas Decaens Creteil, France Email: [email protected] KEY POINTS • Compared to the incidence of hepatitis B virus (HBV) and hepatitis C virus (HCV), alcohol consumption is increasing. The incidence of alcohol-related hepatocellular carcinoma (HCC) is probably under-estimated with regard to worldwide alcohol consumption. • Alcohol is now well-defined as a liver carcinogen. Although the general mechanisms of alcoholrelated carcinogenesis are similar to those of viral carcinogenesis, there are many differences in the fine details. However, only a few studies have been designed to compare alcohol-related with viral-related HCC. • The prognoses of patients with HCC who are referred to hepatologists do not seem to vary significantly. However, liver-transplantation data show that ALD patients have less access to treatment compared to other patients. There may also be discrimination against other treatments for HCC in ALD patients, though these comparisons have not been made as yet. Table 2 INTRODUCTION Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer-related death1. In 70–90% of cases, HCC develops on underlying liver cirrhosis or inflammation. Worldwide, 75–80% primary liver cancers are attributable to chronic viral infections of either HBV (50–55%) or HCV (25–30%). In contrast, the percentage of alcohol-related HCCs is not well defined. According to a World Health Organization (WHO) report2, the percentage of deaths from liver cancer attributable to alcohol is 30.3%. Thus, we can suppose that 25–30% of HCCs are related to alcohol consumption. However, the overall 5-year incidence of HCC is 10% for HBV infection, 30% for HCV infection, 20% for hemochromatosis-related liver damage, but only 8% for alcohol-induced cirrhosis. HOW TO ATTRIBUTE HCC TO ALCOHOL CONSUMPTION? In the setting of cirrhosis, there are no specific biological markers that suggest an alcoholic etiology of HCC (compared to HBV and HCV infections). Information on alcohol intake must be collected through interviews with patients, which are open to error regarding methodologies used for acquisition (for example: x beers per day and not y g/day), as well as the unreliability of patients’ recall and/or reporting. Moreover, data collection can be prone to mistakes made by physicians as well as underestimations of alcohol consumption made by patients. As shown in Figure 1, the geographical distribution of alcohol use is very variable worldwide. Although global alcohol consumption seems to be stable, according to the WHO 5-year change-in-alcohol use 2001–2005 report 2, over a longer period of time, alcohol consumption has increased in many countries. For example, in China, where almost all cases of HCC are supposed to be related to HBV, the rate of alcohol production increased by nine-fold between 1978 and 1997. In a Chinese survey, annual ethanol consumption among adults (aged 15+) was 4.5l, and heavy drinkers accounted for 6.7% of the sample3. As the current Chinese population is ~1.3 billion, heavy drinkers represent ~87.1 million people (compared to 14 million in the USA). Alcohol consumption is also increasing in other countries, such as Japan, South Korea, USA, Russian Federation, and the UK. These data are worrying because we know that per capita alcohol consumption is correlated with alcoholic cirrhosis in various populations4. Compared to the increase in alcohol consumption, it is of note that HBV infection5 and HCV infection6 are currently decreasing. Heavy alcohol intake (>50–70 g/day) for prolonged periods (5–10 years) is a well-recognized risk factor for HCC, and its risk (odds ratio) increases linearly when alcohol intake is >60 g/day for men and women 132 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 133 (Figure 2)7. Moreover, alcohol is also recognized as a cofactor in the development of HCC. An additive effect has been found between alcohol intake of ≥60 g/day and each hepatitis-virus infection. This effect is more pronounced for HCV infection and has been confirmed in different studies. In patients with nonalcoholic steatohepatitis (NASH), alcohol consumption has been recognized as the most significant factor associated with the risk of developing HCC. long-term administration of ethanol to rodents, these enzyme-altered foci are observed to contain quiescent hepatic progenitor cells. In ALD, TNFα and TGFβ1 are markedly up-regulated. TNFα is an important stimulator of oval-cell proliferation: it triggers JNK1 but also activates NFκB, which then activates cellsurvival machinery. In addition, TGFβ1 is involved in the epithelial–mesenchymal transition (EMT), which plays a role in carcinogenesis. The proportion of HCCs attributable to alcohol consumption varies across the world, from 45% in Europe and the USA, to 20% in Japan, and 0% in Africa and Asia8. These variations are possibly due to geographical variations in alcohol consumption (Figure 1) but may be also due to under estimations of alcohol-related HCC in countries where HCV or HBV incidence is still high. In fact, it is surprising to note that Japan and the USA have the same per capita alcohol consumption (8 and 9.4, respectively) but only 20% of Japanese HCCs are reported to be related to alcohol compared to 45% in the USA8. Moreover, South Korea and France have the same per capita alcohol consumption (14.8 and 13.7, respectively), but alcohol-related HCC is reported as 0% in South Korea compared to 70% in France. However, it is impossible to rule out a genetic susceptibility to alcohol-related HCC, which could be higher in USA and French populations compared to Asian. Patterns of alcohol consumption are also important because we know that binge drinking is associated with an elevated incidence of sudden death. c.Retinoid depletion Chronic alcohol consumption decreases vitamin A and retinoid-acid concentrations in the liver. In addition, there is a strong inverse relationship between vitamin A concentration and later development of HCC. The main reason for decreased retinoid acid is increased catabolism by ethanol-induced CYP2E1. This decrease is associated with increased expression of the AP1 transcriptional complex (JUN and FOS), resulting in hepatic hyperproliferation and decreased apoptosis, which may contribute to carcinogenesis. GENETIC SUSCEPTIBILITY As yet, only case-control studies or candidate-gene series have identified genetic-risk factors for HCC in alcoholic patients. These studies have mainly identified polymorphisms in superoxide dismutase (SOD), liver-iron overload, human hemochromatosis (HFE), glutathione peroxidase, myeloperoxidase, methylenetetrahydrofolate reductase (MTHFR) and, more recently, patatin-like phospholipase A3 (PLPLA3). Among these risk factors, only the first four seem to be specific to alcohol-related HCC; the others are also associated with HCV- or HBV-related HCC. Despite the incontestable usefulness of these studies, we now need global studies to improve our understanding of the associations between HCC and alcohol. No genome-wide association study (GWAS) has been published yet that independently identifies the genetic risk factors for HCC in alcoholic liver disease. Although GWAS data that evaluate the genetic risks for HCC are available, they only provide information for chronic HBV or HCV infection. MECHANISMS OF CARCINOGENESIS In the past, alcohol was considered more as a co-carcinogen than a direct carcinogen, but recent studies have clearly identified ethanol as a liver carcinogen by itself. General mechanisms of alcohol carcinogenesis involve acetaldehyde formation, oxidative-stress induction, formation of liver cirrhosis, retinoid depletion, and DNA-methylation deficiency (reviewed in Seitz et al.9 and summarized in Figure 3). In the liver, acetaldehyde is quickly metabolized and does not play a major role in HCC. a.Oxidative stress Oxidative stress is an important factor in hepatocarcinogenesis, whatever the etiology of liver disease. Oxidative stress leads to the generation of reactive oxygen species (ROS). Ethanol-mediated ROS formation may be caused by several factors: • Chronic ethanol consumption causes a 10–20-fold increase in hepatic cytochrome P450 2E1 (CYP2E1) in animals and humans, resulting in increased ROS production by the CYP2E1-dependent microsomal mono-oxygenase system. •TNFα production can increase ceramide levels, leading to increased mitochondrial ROS production. •Hepatic iron overload (increased by chronic alcohol consumption) increases ROS. ROS induces the generation of lipid-peroxidation products, such as malondialdehyde and 4-hydroxynonenal (4-HNE), which can react with DNA bases to form exocyclic DNA adducts that are highly mutagenic. b. Cirrhosis Among the pre-neoplastic lesions found in the liver are enzyme-altered foci and dysplastic nodules. After The retinoid pathway has been shown to play an important role in HBV- and HCV-related HCC, and a direct interaction between viral proteins has been shown. Moreover, it has been proposed that HBx may induce promoter methylation of RAR-beta via up-regulation of DNA methyltransferases 1 and 3a. d.DNA-methylation deficiency Methylation of genes is an important tool in controlling gene expression: hypermethylation induces a silencing effect and hypomethylation results in increased gene expression. Alcohol consumption interferes with these methylation processes, mainly by inhibiting S-adenosyl-L-methionine (SAMe) synthesis, which is the universal methyl-group donor and enzyme activator in methyl-transfer reactions. It has recently been shown that, depending on the HCC risk factors (HBV, HCV, or alcohol related), the DNA methylation profile differs10. Moreover, the methylation profile of a set of eight genes has been shown to distinguish the clinical features of HCC, such as gender, age, HBV-positive tumors, pathological grade, and alcohol intake when methylation of the MGMT gene significantly higher. e. Genotoxicity Few data on genome-wide HCC analyses show the influence of etiology on the underlying liver disease. However, as mentioned above, it is possible that alcohol consumption is under-recorded in series that have a high incidence of viral-related HCC. It has been reported that specific deletion of the 4q34-35 region is associated with heavy alcohol intake, even if the patient is infected by HCV. However conflicting results have been published. Unsupervised global transcriptome analysis of HCC did not identify significant differences between the underlying liver pathology. However, direct comparison of transcriptome analysis between HCV and alcohol-related HCC has revealed some differences11. f. Other mechanisms Alcohol-induced CYP2E1 may interfere with the metabolism of certain pro-carcinogens, such as nitrosamines, polycyclic hydrocarbons, and aflatoxins. This interaction increases the carcinogenic effect of these pro-carcinogens (except for nitrosamines simultaneously administered with ethanol). PROGNOSIS AND TREATMENT OF ALCOHOL-RELATED HCC None of the frequently used HCC classification systems take into account the etiology of liver disease. In fact, no significant differences have been found in liver function between ALD and viral hepatitis12. Moreover, even though the etiology of liver disease has been defined as a prognostic factor in some studies, the power of this finding is small. A patient’s prognosis depends on access to treatment. Compared to HBV-, HCV-, or NASH-related cirrhosis, ALD is considered to be self-inflected, and the general public and even some professionals question the degree of priority given to these patients. In a study on adherence to AASLD criteria for referral for liver transplantation, it has been shown that patients with ALD have a significantly poorer odds ratio of receiving 134 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE a transplant, even after excluding patients who are still actively drinking13. In this study, HCC was not significantly associated with adherence to guidelines. The potential prejudice of the general public and of some medical professionals towards these patients probably induces a generally worse prognosis for alcohol-related HCC compared to virally-related HCC. THE INTERNATIONAL LIVER CONGRESSTM 2012 135 Figure 3: Simplified scheme of the mechanisms involved in ALD -related carcinogenesis (adapted from Seitz H.K. et al.9) Figure 1: Total of adults (aged 15+) per capita consumption of alcohol (L of pure alcohol), in 20052 REFERENCES Figure 2: Odds ratio for HCC according to alcohol intake and the presence of HBV or HCV, obtained by fitting spline regression models that included age and residence as covariates, in the Brasilia HCC study7. Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. Global status report on alcohol and death. www.who.int/substance.../global_alcohol report/msbgsruprofiles.pdf, 2011. Contains major reference about alcohol consumption in the world and by country. Cochrane J, Chen H, Conigrave KM, et al. Alcohol use in China. Alcohol Alcohol 2003;38:537-42. Corrao G, Ferrari P, Zambon A, et al. Are the recent trends in liver cirrhosis mortality affected by the changes in alcohol consumption? Analysis of latency period in European countries. J Stud Alcohol 1997;58:486-94. Hepatitis B. http://www.who.int/csr/disease/hepatitis/whocdscsrlyo20022/en/index.html, 2002. Deuffic-Burban S, Deltenre P, Louvet A, et al. Impact of viral eradication on mortality related to hepatitis C: a modeling approach in France. J Hepatol 2008;49:175-83. Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 2002;155: 323-31. Contains proof of dose effect for alcohol consumption and additive effect of HCV or HBV infection. Bosch FX, Ribes J, Diaz M, et al. Primary liver cancer: Worldwide incidence and trends. Gastroenterology 2004;127:S5-S16. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007;7:599-612. Major review about molecular mechanism of alcohol-related carcinogenesis. Hernandez-Vargas H, Lambert MP, Le Calvez-Kelm F, et al. Hepatocellular carcinoma displays distinct DNA methylation signatures with potential as clinical predictors. PLoS One 2010;5:e9749. Derambure C, Coulouarn C, Caillot F, et al. Genome-wide differences in hepatitis C- vs alcoholism-associated hepatocellular carcinoma. World J Gastroenterol 2008;14:1749-58. Herold C, Regn S, Ganslmayer M, et al. Can quantitative tests of liver function discriminate between different etiologies of liver cirrhosis? Dig Dis Sci 2002;47:2669-73. Julapalli VR, Kramer JR, El-Serag HB. Evaluation for liver transplantation: adherence to AASLD referral guidelines in a large Veterans Affairs center. Liver Transpl 2005;11:1370-8. 136 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE LONG-TERM MANAGEMENT OF ALCOHOLIC LIVER DISEASE EVALUATION AND SELECTION OF CANDIDATES FOR LIVER TRANSPLANTATION Georges-Philippe Pageaux Montpellier, France E-mail: [email protected] KEY POINTS • Alcoholic cirrhosis, with or without hepatocellular carcinoma, is the second cause of liver transplantation (LT) in Europe and United States. • When we take into account the usual criteria for success in LT (patient and graft survival, rejection and infection rates), alcoholic liver disease (ALD) is a good indication for transplantation, with 1- and 5-year survival rates of 84% and 73%, respectively. • Some disparities are observed at the referral level when patients with ALD are compared with non ALD patients. • Recent results support the current procedure of giving priority for organ allocation to the sickest patients. • The pre-transplant investigation is based on assessing the patient’s conditions and alcoholrelated co-morbidities that might limit the potential for successful transplantation. • The so-called 6-month rule (a duration of 6 months of abstinence before LT) has not demonstrated its ability to predict relapse after LT, and should no longer be the definite rule and should not be the determining factor for graft access. • The participation of a team specialized in addiction problems in this period should be recommended and their involvement should be based on a contract of care. • The alcoholic patient, candidate for LT, should be considered as suffering from a double pathology, both hepatic and alcoholic. The French Committee of Health Education estimates that the number of people having excessive alcohol consumption in France is about 10% of the general population. It is estimated that the number of registered deaths per year in France, which are related to excessive and regular alcohol consumption is 45,000. There are 8,000 to 10,000 annual registered deaths linked to a complication of alcoholic cirrhosis. Alcoholic liver disease (ALD) is the most common cause of cirrhosis in western countries. Consequently, alcoholic cirrhosis, with or without hepatocellular carcinoma, is the main cause of liver transplantation (LT) in France and the second in Europe and United States. The controversy surrounding ALD as indication for LT has already stirred debate regarding the duration of abstinence before transplantation and the risk of recurrence, resulting in several recommendations for LT indications. Guidelines evolve according to prevailing opinions, but there is a consensus that, to the extent that there is a multidisciplinary approach to the patient, ALD is as good indication for LT as are other chronic liver diseases. When LT is considered in a patient with ALD, several points need to be emphasized: the under-referral of these patients to liver transplant programs, choosing the optima timing for transplantation, the pretransplant abstinence, the pre-transplant evaluation. In patients with end-stage ALD, the 5-year survival without LT is < 25%, when it is > 70% if LT is performed. Thus, ALD has become one of the main indications for LT. It emerges from most studies that when we take into account the usual criteria for success in LT (patient and graft survival, rejection and infection rates), ALD is a good indication for LT. According to the European liver transplant registry, survival after TL for ALD BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 137 is 84%, 73%, and 58% at 1, 5, and 10 years, respectively, significantly higher than in viral and cryptogenic cirrhosis (1). However, the main issue is the likelihood of relapse and its influence on the outcome, because it is the possibility of returning to alcohol use that separates patients with ALD from those with other forms of chronic liver disease. Consequently, some disparities are observed at the referral level when patients with ALD are compared with non ALD patients (2). Thus, less than 10% of the 70-100,000 patients per year who develop decompensated cirrhosis due to ALD in United States are referred for transplant (3). The attitude of physicians to alcohol addiction is likely an influence on the referral of ALD patients for LT. Some of them hold pejorative views of patients who suffer from alcohol abuse and dependence. Others are confused about when they should refer their patients for an LT evaluation and about whether a specific interval of abstinence is needed before any referral (4) Concerning the timing of LT in ALD patients, recent results support the current procedure of giving priority for organ allocation to the sickest patients. A recent randomized trial has demonstrated that immediate listing for LT did not show a survival benefit compared with standard care for Child-Pugh stage B alcoholic cirrhosis (5). In addition, immediate listing for transplantation increased the risk for extra-hepatic cancer. In contrast, a retrospective analysis of the UNOS database showed that ALD patients with relatively low MELD scores in the range of 9 to 11 derived a survival benefit (6). Patients with severe acute alcoholic hepatitis present particular challenges to transplant teams because they have obviously consumed alcohol in the previous month. A recent French, multicenter, case-control analysis about patients presenting their first episode of severe, cortico-resistant acute alcoholic hepatitis demonstrated that they had an excellent intermediate-term survival and a low frequency of harmful drinking after LT (7). In addition to evaluating the severity of the liver disease, the pre-transplant investigation is based on assessing the patient’s conditions and co-morbidities that might limit the potential for successful transplantation. Among the numerous extra-hepatic complications of alcoholism, we have to focus on the followings during the pre-transplant evaluation : pancreatitis, neurological manifestations, heart disease, renal disease, poor nutritional status, and cancers. Several studies have demonstrated a close relationship between alcohol consumption and acute/chronic pancreatitis. In the setting of transplantation, one must consider the probability of the sequels of previous manifestations of the disease such as abcess, venous thrombosis, adherences, which could make more difficult the surgical transplant procedure. Moreover, carcinoma of the pancreas may occur with increased frequency in alcoholic patients, although it correlates better with cigarette smoking than with alcohol consumption. The exclusion of pancreatic carcinoma in a patient with chronic alcoholic pancreatitis may be a difficult diagnostic problem. Thus, high quality imaging tests are necessary for the pre-transplant evaluation. Wernicke’s encephalopathy and Korsakoff’s syndrome are nutritional disorders caused by thiamine deficiency. Chronic alcohol consumption can result in thiamine deficiency by causing inadequate nutritional thiamine intake, decreased absorption of thiamine from the gastroeintestinal tract, and impaired thiamine utilization in the cells. Mental confusion in the main characteristic of these diseases, sometimes difficult to distinguish from hepatic encepalopathy. Treatment consists of parenteral thiamine, but in the majority of patients with Korsakoff’s syndrome, recovery is incomplete. This situation represents a contraindication for LT. Alcoholism is also responsible for dose-related injury to the peripheral nervous system. Direct cumulative neurotoxicity from alcohol, nutritional and vitamin deficiencies associated with alcoholism, and liver cirrhosis itself each probably contribute to this peripheral neuropathy. Resolution of alcoholic neuropathy following LT has been reported. Thus, this manifestation does not request a contraindication to transplant. However, it must be emphasized that calcineurin inhibitors immunosuppressive agents used after transplantation have some degree of dose-related peripheral neurotoxicity which can worsen a pre-transplant neuropathy with some degree of disablement. 138 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE Chronic alcohol consumption can lead to progressive cardiac dysfunction, resulting in congestive cardiomyopathy. Alcoholic cardiomyopathy is characterized by an increase in myocardial mass, dilation of the ventricles, and wall thinning. Changes in ventricular function may depend on the stage, in that asymptomatic stage is associated with diastolic dysfunction, whereas systolic dysfunction is a common finding in symptomatic patients, leading to heart failure in latter stages. Moreover, cirrhosis per se is associated with impaired cardiac contractility. This phenomenon of attenuated cardiac responsiveness to stimuli is termed cirrhotic cardiomyopathy. The emergence of LT as an effective treatment for alcoholic cirrhosis has led to the recognition of previously subclinical cardiomyopathy and congestive heart failure accounts for significant mortality and morbidity after this procedure. Coronary heart disease which is associated with excessive alcohol consumption needs to be extensively examined in the setting of transplantation. Numerous clinical and experimental studies have demonstrated that excessive alcohol consumption has deleterious effects on the kidney. A variety of tubular defects have been described in these patients, often reversible with abstinence. On the other hand, IgA nephropathy has been demonstrated in chronic alcoholism, with irreversible lesions responsible for asymptomatic proteinuria. This raises the possibility that alcoholic cirrhosis itself and the attendant abnormalities in renal function may predispose the liver transplant patient to permanent renal damage when treated with calcineurin inhibitors. The progression of alcoholic liver disease to decompensated cirrhosis stage has profound effects on hepatic metabolism and ultimately, on body composition and weight. This results in profound nutritional changes that include weight loss and evidence for protein caloric malnutrition. Moreover, malnutrition is an additional developmental factor in the functional and structural muscle damage induced by chronic ethanol consumption. The impact of nutritional status on outcomes after LT has been studied. Poor pre-operative nutritional status was associated with longer intensive care unit stays and increased likelihood of posttransplant infections. There is a clear association of heavy alcohol consumption with cancers of mouth, larynx, pharynx, and oesophagus. Moreover, alcoholics are also often heavy smokers. It is crucial to rule out any neoplastic disease or pre-neoplastics conditions during the pre-transplant evaluation, since ALD patients appear to have a higher incidence of malignancies after LT, especially oropharyngeal carcinomas. The first approach to ensuring abstinence after transplantation has been to try to select during the pretransplant period only those patients likely to maintain abstinence. A recent meta-analysis identified 3 pretransplant factors associated with alcoholic relapse after LT: lack of social support, a family history of alcoholism, and less than 6 months of abstinence from alcohol (8). There is a lack of consensus for the duration of abstinence from alcohol, as well as what constitute good psychosocial criteria for listing for LT. Abstinence is essential and the pre-transplantation period should be used for strengthening the motivation to end alcohol use. This discontinuation commits the patient to a therapeutic program which may prevent post-transplantation relapse. However, the so-called 6-month rule (a duration of 6 months of abstinence before LT) has not demonstrated its ability to predict relapse after LT, and should no longer be the definite rule and should not be the determining factor for graft access. A 3- or 6-month period of abstinence before transplantation may be justified when carried out as part of a larger strategy for management of alcohol dependence. It should take into account time for motivation, achievement of abstinence, and for the prevention of relapse, and should never be carried out under the pretext of coercion. Moreover, alcohol withdrawal is sometimes associated with recovery of liver function : three months of abstinence may unmask those with truly irreversible ALD (9). Patients with a lack of social support, personality disorders, or a pattern of non-adherence should be listed only with reservation. The second approach to reducing the risk of post-transplantation drinking is to initiate alcoholism therapy before transplantation. Results are disappointing (10). It appears that alcohol-dependent liver transplant candidates struggle with total abstinence before transplantation. Treatment interventions to effect robust and lasting sobriety in this population are limited. It is also important to emphasize that the severity of liver disease in these patients is so substantial, that a rigorous approach is quite difficult. THE INTERNATIONAL LIVER CONGRESSTM 2012 139 LT for ALD should be a central event in the management of the alcoholic patient, imposing some responsabilities on the medical team in its follow-up care. The participation of a team specialized in addiction problems in this period should be recommended and their involvement should be based on a contract of care. Without being a written document, this contract may be seen as a therapeutic alliance in which empathy plays a key role. In summary, it is possible to place patients with ALD on the waiting list under two conditions: • that there is a pre-transplantation assessment with particular attention paid to the presence of: lesions related to alcohol consumption or smoking; extra-hepatic lesions, such as cancers and precancerous conditions including oropharyngeal, bronchial, esophageal; respiratory and cardiovascular pathology. • that alcoholic care management is started as early as possible by a team specialized in addictive behaviors. Many studies suggest that short- and mid-term results of LT for ALD are not influenced by alcohol relapse. However, beyond five years, it seems that long-term survival is reduced because of other target-organ damage of both alcohol and tobacco, especially aero-digestive malignancies, which are greater causes of morbidity and mortality than is recurrent ALD. Finally, we have to keep in mind the dichotomy between ethical issues and public perceptions, that is well illustrated in the debate about LT for patients with ALD : does the general public support organ donation for patients with ALD? Societal attitudes towards these patients must change. The alcoholic patient, candidate for LT, should be considered as suffering from a double pathology, both hepatic and alcoholic. REFERENCES Burra P, Senzolo M, Adam R, et al. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR. Am J Transplant 2010;10:138-148 Julapalli VR, Kramer JR, El-Serag HB, et al. Evaluation for liver transplantation: adherence to AASLD referral guidelines in a large Veterans Affairs center. Liver Transpl 2005;11:1370-1378 Kotlyar DS, Burke A, Campbell MS, et al. A critical review of candidacy for orthotopic liver transplantation in alcoholic liver disease. Am J Gastroenterol 2008;103:734-743 Lucey MR. Liver transplantation in patients with alcoholic liver disease. Liver Transpl 2011; 17:751-759 Vanlemmens C, Di Martino V, Milan C, et al. Immediate listing for liver transplantation versus standard care for Child-Pugh stage B alcoholic cirrhosis: a randomized trial. Ann Intern Med 2009;150:153-161 Lucey MR, Schaubel DE, Guidinger MK, and al. Effects of alcoholic liver disease and hepatitis C infection on waiting list and posttransplant mortality and transplant survival benefit. Hepatology 2009;50:400-406 Mathurin P, Moreno C, Samuel D, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011; 365:1790-1800 Dew MA, DiMartini AF, Steel J, et al. Meta-analysis of risk for relapse to substance use after transplantation of the liver or other solid organs. Liver Transpl 2008;14:159-172 Veldt BJ, Lainé F, Guillygomarc’h A, et al. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J Hepatol 2002;36:93-98 Weinrieb RM, Van Horn DHA, Lynch KG, et al. A randomized, controlled study of treatment for alcohol dependence in patients awaiting liver transplantation. Liver Transpl 2011;17:539-547 140 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE PATIENTS WITH ALCOHOLIC LIVER DISEASE AND LIVER TRANSPLANTATION: SPECIFIC ISSUES Patrizia Burra Padova, Italy E-mail: [email protected] KEY POINTS • Outcomes of liver transplantation for alcohol-related cirrhosis are comparable with those of liver transplantation for other aetiologies. • Most transplant programs in the US and Europe consider acute alcoholic hepatitis a contraindication to liver transplantation. However early liver transplantation in selected patients with a first episode of severe alcoholic hepatitis not responding to medical therapy has been shown to improve survival. • The role of the length of pre-transplantation abstinence, the so called “6-month rule”, as predictor of post-transplantation abstinence is still controversial. • A psycho-social assessment to establish the likelihood of long-term abstinence after liver transplantation should be performed in patients with alcoholic liver disease considered potential candidates for liver transplantation. • Alcohol relapse after liver transplantation for alcoholic cirrhosis ranges between 10% and 50% in up to 5 years follow-up, according to the method used to assess alcohol relapse. • Overall quality of life and employment levels appear similar between patients transplanted for alcoholic and non-alcoholic liver disease. However the incidence of deaths due to all social causes has been shown to be double in patients with an alcoholic etiology of liver disease, compared to other etiologies. INTRODUCTION Alcoholic liver disease is one of the most common causes of cirrhosis and indications for liver transplantation in Europe and North America [1-3]. Despite the results of liver transplantation for alcohol-related cirrhosis are comparable with those of liver transplantation for other aetiologies, alcoholic liver disease has been considered a controversial indication to liver transplantation. The reluctance to transplant alcoholics stems in part from the view that alcoholics bear responsibility for their illness [3] and there is also the perception that the alcoholic person is likely to relapse into alcohol use after transplantation and thereby damage the allograft. ALCOHOLIC LIVER DISEASE AND INDICATION FOR LIVER TRANSPLANTATION Liver transplantation in patients with alcoholic cirrhosis was first acknowledged in 1983 [4]. Poynard et al. [5] showed that there was a survival benefit when patients with advanced de-compensation (Child-TurcottePugh score ranging between 11 and 15) underwent transplantation, whereas there was no survival benefit when alcoholic patients with better compensated liver function were transplanted. Most of the patients with severe alcoholic hepatitis, whether occurring in the previously healthy liver or in patients with established cirrhosis, fail to recover despite abstinence and maximal medical therapy. Most transplant programs in the US and Europe consider acute alcoholic hepatitis a contraindication to liver transplantation [6, 7]. However a recent multicenter study by Mathurin et al. [8] showed that early liver transplantation can improve survival in patients with a first episode of severe alcoholic hepatitis not responding to medical therapy. Twenty-six patients with no prior episode of alcoholic hepatitis and with no response to medical therapy or rapid worsening of liver function despiite medical treatment were selected after an adequate psychiatric and social evaluation. The cumulative 6-month survival rate was higher among patients who received early transplantation than among those who did not (77±8% vs. 23±8%; p<0.001). After 2 years of follow-up this benefit was mantained (p=0.004). Three patients presented alcohol relapse. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 141 Chronic HCV infection often coexists with alcoholic liver disease and the combination may act synergistically to cause liver disease. Consequently, combined alcoholism and HCV infection are common among patients under evaluation for liver transplantation. It has been shown that HCV-positive who have an alcohol intake greater than 50g per day develop cirrhosis compared to HCV-positive patients with a lower alcohol intake [9]. Therefore, it is incumbent on the transplant center to evaluate for alcoholism in patients wherein HCV is the considered diagnosis, and vice versa. Primary hepatocellular carcinoma may complicate alcoholic cirrhosis and the risk is greater when there is a concomitant chronic viral infection, especially in males [10]. The candidate’s management is based on the assessment of the accepted criteria for liver transplantation in the presence of hepatocellular carcinoma [11]. ASSESSING THE SEVERITY OF LIVER DISEASE AND TIMING FOR LIVER TRANSPLANTATION Assessment of the risk of dying among patients with alcoholic cirrhosis depended, in the past, on the ChildTurcotte-Pugh (CTP) classification. In more recent years, a new prognostic system has been developed, called Model for End-Stage Liver Disease (MELD), which predicts liver disease severity on the basis of serum creatinine, serum total bilirubin and INR [12, 13]. Two other prognostic models have been developed for patients with alcoholic liver disease, the first developed by Poynard (“Beclere model”), using only variables that are readily available to the clinician (serum bilirubin, albumin, age in years and encephalopathy) [14]; the second model, the Birmingham model, is based on a similar methodology and uses serum bilirubin, blood urea, serum albumin, ascites, bacterial peritonitis [15]. Prognostic models are useful in identifying variables associated with a given outcome but must be used with caution in individual patients, as confidence intervals are wide and application of models derived from one population may not be necessarily valid in another group. In addition to evaluating the severity of the liver disease and its complications, the pre-transplant investigation is based on assessing the patient’s general health, focusing on conditions and co-morbidities such as pancreatitis, central and peripheral neuropathy, heart disease, myopathy, renal insufficiency or poor nutritional status that might limit the potential for successful operation [16]. The role of the length of pre-transplantation abstinence, the so called “6-month rule”, as predictor of posttransplantation abstinence is still controversial [17-21]. There is however a subset of patients with endstage liver disease and alcohol dependence who might be identified before liver transplantation as likely to remain abstinent after liver transplantation. A multidisciplinary approach that evaluate not only medical but also psychological suitability for liver transplantation is then mandatory. A psycho-social assessment to establish the likelihood of long-term abstinence after liver transplantation should be performed in patients with alcoholic liver disease considered potential candidates for liver transplantation. Since alcohol abuse and dependence may be associated with personality disorders, depression, anxiety, poly-substance abuse and other psychiatric disorders, a psychiatric evaluation may be necessary [22]. OUTCOMES AFTER LIVER TRANSPLANTATION FOR ALCOHOLIC LIVER DISEASE Survival Survival of patients transplanted for alcoholic cirrhosis is comparable with the situation in patients transplanted for non-alcoholic cirrhosis [19]. At Padua Liver Transplant Centre the cumulative survival rates at 3 and 5 years after transplantation for alcoholic liver disease were identical to those observed in patients transplanted for non-alcoholic liver disease. When the group of alcoholic cirrhosis patients was divided according to anti-HCV positive or negative status prior to transplantation, the cumulative survival was not statistically different [23]. Moreover, the presence of the histological markers for acute alcoholic hepatitis in the explant was not associated with reduced survival after transplantation surgery [21]. 142 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 143 In a recent study based on ELTR (European Liver Transplant Registry) database, it has been demonstrated that patient survival at 1, 3, 5 and 10 years from first transplantation was 84%, 78%, 73%, 58%, significantly higher in alcoholic liver disease patients compared to HCV and HBV-relate liver disease recipients (82%, 74%, 70%, 60%) and cryptogenic cirrhosis patients (78%, 73%, 69%, 61%) (log rank p = 0.04 and p = 0.05, respectively). When alcoholic liver disease patients were analysed according to HCV or HBV infection, patient survival at 1, 3, 5 and 10 years from first transplantation was 84%, 75%, 65%, 52%, respectively, in alcoholic liver disease with concomitant HCV infection group, significantly lower than 89%, 85%, 81%, 64%, respectively, observed in alcoholic liver disease with concomitant HBV infection patients (log rank p = 0.0002). The incidence of deaths due to all social causes was double in patients with an alcoholic etiology of liver disease with or without viral infection, compared to other etiologies (1.3% alcoholic liver disease and alcoholic liver disease with concomitant HCV or HBV infection vs. 0.7% HCV or HBV and 0.4% cryptogenic cirrhosis, respectively; p = 0.03). In detail, transplanted patients or previous alcoholic liver disease had double the incidence of deaths for suicide compared to viral etiology, p = 0.02 [24]. Patients transplanted for alcoholic liver disease may have an higher incidence of cardiovascular events compared to patients transplanted for other causes of liver disease. It was recently demonstrated that cardiovascular events were the cause of death in 8% of patients transplanted for alcoholic liver disease with and without associated viral infection and in 5.3% of patients transplanted for HCV or HBV cirrhosis, and the difference was statistically significant [24]. Alcohol relapse after liver transplantation With the term “relapse” is generally defined any alcohol intake occurring after liver transplantation. Studies which have evaluated alcohol relapse after liver transplantation for alcoholic cirrhosis have reported a wide range of frequencies ranging from 10% to 50% in up to 5 years follow up [21, 25]. However most of the studies evaluating alcohol relapse after liver transplantation are based on retrospective analysis of routine screening tests, questionnaires or interviews with patients and/or family during routine follow-up, with a consequent potential underestimate of patients’ real drinking habits. De novo neoplasms An increased risk of de novo malignancies after liver transplantation has been reported to rise from 6% to 55% at 15 years after liver transplantation and to account for a significant risk of late death [32]. An overall incidence of oropharyngeal squamous cell carcinoma of 17% in alcohol-induced cirrhosis transplant patients was reported [33]. In another series of patients who underwent liver transplantation for alcoholic liver disease, an incidence of 4.2% of oropharyngeal and esophageal malignancies were seen between 8-40 months after surgery [34]. In a study based on 51 patients with alcoholic liver disease who underwent strictly medical and psychological evaluation before and after liver transplantation, alcohol abuse was recorder in 60% and alcohol dependence in 40% of them before transplantation. Alcohol relapse was observed in 33% of transplanted patients, 64% of who were occasional and 36% were heavy drinkers. The admission of alcoholism by the patient and his/ her family prior to transplantation significantly predicted abstinence after transplantation [26]. The incidence of the de novo tumors as cause of death was significantly higher in alcoholic compared with non-alcoholic etiology of the primary liver disease. Among solid organ tumors, 2% of patients with viral cirrhosis developed oral or upper GI tract tumors compared to 5.4% of patients with alcoholic liver disease and the difference was statistically significant [24]. The prevalence of diabetes mellitus (10%), and hypertension (33%) are comparable with patients transplanted for other aetiologies [30]. Te cerebral blood flow may also be impaired after liver transplantation since many functional alterations in brain physiology are seen in alcoholic cirrhotic patients. Usually these abnormalities are reversed after liver transplantation, but a reduction in the frontal cerebral blood flow may persist for up to 12 months after surgery [31]. Combining results from many studies is evident that from a third to half of the alcoholic transplant recipients start drinking again after transplantation often within the first year after surgery; amongst these nearly 10% resume drinking in an abusive or dependent fashion [27]. Quality of life and adherence to medical prescriptions Whatever the reason for liver transplantation, quality of life improves after surgery in most domains [35]. Overall quality of life and employment levels appear similar between patients transplanted for alcoholic and non-alcoholic liver disease [36]. Acute and chronic rejection Patients transplanted for alcoholic cirrhosis experience fewer episodes of acute cellular rejection after liver transplantation compared to patients transplanted for other reasons [28, 29]. Histologically-proven acute cellular rejection was reported in 14% of patients 23-180 days after liver transplantation for alcoholic cirrhosis [23]. Adherence of patients suffering from alcoholic cirrhosis is still under discussion. After liver transplantation no difference between patients with or without alcohol relapse concerning compliance with medication, incidence of rejection or adherence to check-ups were reported [37]. They appear to return to society to lead active and productive lives, despite they seem less likely to be involved in structured social activities than patients transplanted for non-alcoholic liver disease [38]. Chronic ductopenic rejection is also very uncommon in alcoholics receiving liver transplants. In Padua Liver Transplant Centre, since November 1990, 415 patients have undergone 480 liver transplantations. Eighty of whom were transplanted for alcoholic liver disease either alone or in combination with viral hepatitis or hepatocellular cancer. Among 312 long-term survivors, chronic rejection was seen in 6 (5%). CONCLUSION In conclusion, alcoholic cirrhosis is a widely accepted indication for liver transplantation, whereas the experience of transplantation in patients with acute alcoholic hepatitis is limited to a restricted number of patients with specific slection criteria. Medical complications following liver transplantation Infections are common after liver transplantation for alcoholic liver disease. Bacterial infections seem to be more frequent than in patients transplanted for other causes. The incidence of cytomegalovirus infection was reportedly 14.3% in patients transplanted for alcoholic cirrhosis, which is no different from the 25% incidence observed in patients transplanted for other causes. The incidence of new-onset insulin-dependent diabetes is reportedly less than 10%, while for hypertension it is around 33%, again much the same as in patients transplanted for non-alcoholic liver disease [30]. Literature data showed that, despite alcohol relapse is ranging between 10% and 50% at 5 years after liver transplantation, graft and patient survival is comparable with patients transplanted for different aetiology. A psycho-social assessment to establish the likelihood of long-term abstinence after liver transplantation and a psychiatric evaluation should be performed in all patients with alcoholic liver disease. The role of the length of pretransplantation abstinence, the so called “6-month rule”, as predictor of posttransplantation abstinence is still controversial. 144 POSTGRADUATE COURSE SYLLABUS Combined alcoholism and HCV infection are common among patients under evaluation for liver transplantation and histological changes of HCV infection are also common in post transplant biopsies from these patients. In addition, the hepatocellular carcinoma may develop on top of cirrhosis, and in this case the candidate’s management is based on the accepted criteria for liver transplantation in the presence of hepatocellular carcinoma. Co-morbidities that might limit the potential for successful operation - such as pancreatitis, central and peripheral neuropathy, heart disease, myopathy, renal insufficiency or poor nutritional status should be assessed during the candidate’s management. Although only about 10% of alcoholic liver allograft recipients resume drinking in an abusive or dependent fashion, efforts to restrict the risks of relapse and graft loss are mandatory. Histological changes are usual mild and liver damage is slow to develop after alcohol relapse but fatty changes and fibrosis are more severe in patients who are heavy drinkers than in occasional drinkers and abstainers. Whether due to a direct effect on the graft or indirectly because of noncompliance or damage to other organs, the effect of histological recurrence due to alcohol recidivism is much less than that seen with some other indications, notably with hepatitis C virus (HCV) infection. Alcoholic patients experience fewer episodes of acute cellular rejection after liver transplantation than patients transplanted for other reasons and chronic ductopenic rejection is also very uncommon. Conversely, cardiovascular complications and infections are common after liver transplantation for alcoholic liver disease as well as the development of de novo malignancies. Lastly, the quality of life and employment levels appear similar or even better between patients transplanted for alcoholic and non-alcoholic liver disease, whereas the compliance of such patients is still under discussion despite no difference between patients with or without alcohol relapse concerning compliance with medication, incidence of rejection or adherence to check-ups have been reported. REFERENCES BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE http://www.eltr.org. http://www.unos.org/donation/index.php?topic=data Neuberger J. Transplantation for alcoholic liver disease: a perspective from Europe. Liver Transpl Surg 1998;4:S51-57. National Institutes of Health Consensus Development Conference Statement: liver transplantation--June 20-23, 1983. Hepatology 1984;4:107S-110S. Poynard T, Naveau S, Doffoel M, Boudjema K, Vanlemmens C, Mantion G, et al. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis using matched and simulated controls: 5-year survival. Multi-centre group. J Hepatol 1999;30:1130-1137. Mutimer DJ, Burra P, Neuberger JM, Hubscher S, Buckels JA, Mayer AD, et al. Managing severe alcoholic hepatitis complicated by renal failure. Q J Med 1993;86:649-656. Veldt BJ, Laine F, Guillygomarc’h A, Lauvin L, Boudjema K, Messner M, et al. Indication of liver transplantation in severe alcoholic liver cirrhosis: quantitative evaluation and optimal timing. J Hepatol 2002;36:93-98. Mathurin P, Moreno C, Samuel D, Dumortier J, Salleron J, Durand F, et al. Early liver transplantation for severe alcoholic hepatitis. N Engl J Med 2011;365:1790-1800. Poynard T, Bedossa P, Opolon P. Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups. Lancet 1997;349:825-832. Schafer DF, Sorrell MF. Hepatocellular carcinoma. Lancet 1999;353:1253-1257. Bruix J, Llovet JM. Prognostic prediction and treatment strategy in hepatocellular carcinoma. THE INTERNATIONAL LIVER CONGRESSTM 2012 145 Hepatology 2002;35:519-524. Merion RM, Wolfe RA, Dykstra DM, Leichtman AB, Gillespie B, Held PJ. Longitudinal assessment of mortality risk among candidates for liver transplantation. Liver Transpl 2003;9:12-18. Wiesner R, Edwards E, Freeman R, Harper A, Kim R, Kamath P, et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology 2003;124:91-96. Poynard T, Barthelemy P, Fratte S, Boudjema K, Doffoel M, Vanlemmens C, et al. Evaluation of efficacy of liver transplantation in alcoholic cirrhosis by a case-control study and simulated controls. Lancet 1994;344:502-507. Anand AC, Ferraz-Neto BH, Nightingale P, Mirza DF, White AC, McMaster P, et al. Liver transplantation for alcoholic liver disease: evaluation of a selection protocol. Hepatology 1997;25:1478-1484. Sherman D, Williams R. Liver transplantation for alcoholic liver disease. J Hepatol 1995;23:474-479. Burra P, Smedile A, Angelico M, Ascione A, Rizzetto M. Liver transplantation in Italy: current status. Study Group on Liver Transplantation of the Italian Association for the Study of the Liver (A.I.S.F.). Dig Liver Dis 2000;32:249-256. Gish RG, Lee AH, Keeffe EB, Rome H, Concepcion W, Esquivel CO. Liver transplantation for patients with alcoholism and end-stage liver disease. Am J Gastroenterol 1993;88:1337-1342. Pageaux GP, Perney P, Larrey D. Liver transplantation for alcoholic liver disease. Addict Biol 2001;6:301-308. Tome S, Lucey MR. Timing of liver transplantation in alcoholic cirrhosis. J Hepatol 2003;39:302-307. Tome S, Martinez-Rey C, Gonzalez-Quintela A, Gude F, Brage A, Otero E, et al. Influence of superimposed alcoholic hepatitis on the outcome of liver transplantation for end-stage alcoholic liver disease. J Hepatol 2002;36:793-798. Walter M, Scholler G, Moyzes D, Hildebrandt M, Neuhaus R, Danzer G, et al. Psychosocial prediction of abstinence from ethanol in alcoholic recipients following liver transplantation. Transplant Proc 2002;34:1239-1241. Burra P, Mioni D, Cecchetto A, Cillo U, Zanus G, Fagiuoli S, et al. Histological features after liver transplantation in alcoholic cirrhotics. J Hepatol 2001;34:716-722. Burra P, Senzolo M, Adam R, Delvart V, Karam V, Germani G, et al. Liver transplantation for alcoholic liver disease in Europe: a study from the ELTR (European Liver Transplant Registry). Am J Transplant 2010;10:138-148. Mackie J, Groves K, Hoyle A, Garcia C, Garcia R, Gunson B, et al. Orthotopic liver transplantation for alcoholic liver disease: a retrospective analysis of survival, recidivism, and risk factors predisposing to recidivism. Liver Transpl 2001;7:418-427. Burra P, Mioni D, Cillo U, Fagiuoli S, Senzolo M, Naccarato R, et al. Long-term medical and psycho-social evaluation of patients undergoing orthotopic liver transplantation for alcoholic liver disease. Transpl Int 2000;13 Suppl 1:S174-178. Tang H, Boulton R, Gunson B, Hubscher S, Neuberger J. Patterns of alcohol consumption after liver transplantation. Gut 1998;43:140-145. Berlakovich GA, Rockenschaub S, Taucher S, Kaserer K, Muhlbacher F, Steiniger R. Underlying disease as a predictor for rejection after liver transplantation. Arch Surg 1998;133:167-172. Farges O, Saliba F, Farhamant H, Samuel D, Bismuth A, Reynes M, et al. Incidence of rejection and infection after liver transplantation as a function of the primary disease: possible influence of alcohol and polyclonal immunoglobulins. Hepatology 1996;23:240-248. Platz KP, Mueller AR, Spree E, Schumacher G, Nussler NC, Rayes N, et al. Liver transplantation for alcoholic cirrhosis. Transpl Int 2000;13 Suppl 1:S127-130. Dam M, Burra P, Tedeschi U, Cagnin A, Chierichetti F, Ermani M, et al. Regional cerebral blood 146 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE flow changes in patients with cirrhosis assessed with 99mTc-HM-PAO single-photon emission computed tomography: effect of liver transplantation. J Hepatol 1998;29:78-84. Haagsma EB, Hagens VE, Schaapveld M, van den Berg AP, de Vries EG, Klompmaker IJ, et al. Increased cancer risk after liver transplantation: a population-based study. J Hepatol 2001;34:84-91. Duvoux C, Delacroix I, Richardet JP, Roudot-Thoraval F, Metreau JM, Fagniez PL, et al. Increased incidence of oropharyngeal squamous cell carcinomas after liver transplantation for alcoholic cirrhosis. Transplantation 1999;67:418-421. Kenngott S, Gerbes AL, Schauer R, Bilzer M. Rapid development of esophageal squamous cell carcinoma after liver transplantation for alcohol-induced cirrhosis. Transpl Int 2003;16:639-641. De Bona M, Ponton P, Ermani M, Iemmolo RM, Feltrin A, Boccagni P, et al. The impact of liver disease and medical complications on quality of life and psychological distress before and after liver transplantation. J Hepatol 2000;33:609-615. Cowling T, Jennings LW, Jung GS, Goldstein RM, Molmenti E, Gonwa TA, et al. Comparing quality of life following liver transplantation for Laennec’s versus non-Laennec’s patients. Clin Transplant 2000;14:115-120. Berlakovich GA, Langer F, Freundorfer E, Windhager T, Rockenschaub S, Sporn E, et al. General compliance after liver transplantation for alcoholic cirrhosis. Transpl Int 2000;13: 129-135. Cowling T, Jennings LW, Goldstein RM, Sanchez EQ, Chinnakotla S, Klintmalm GB, et al. Societal reintegration after liver transplantation: findings in alcohol-related and non-alcohol-related transplant recipients. Ann Surg 2004;239:93-98. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 147 NOVEL TARGETS FOR ALCOHOLIC LIVER DISEASE (ALD) THERAPY IDENTIFIED IN TRANSLATIONAL STUDIES Bin Gao Bethesda, Maryland, USA E-mail: [email protected] KEY POINTS • The mechanisms underlying the pathogenesis of ALD are not fully understood. • Ethanol-mediated hepatotoxicity and activation of innate immunity contribute to the pathogenesis of ALD; however activation of many innate immunity components also promotes liver repair. • Steroid treatment may be beneficial in some ALD patients by inhibiting inflammation; however, such treatment may also block liver regeneration and increase bacterial infection. • Several novel targets that can be used to block liver inflammation in ALD: CXC chemokines, complement, gut microbiota and LPS pathways, osteopontin. • Several novel targets that can be used to promote hepatocyte survival and proliferation in ALD: apoptosis inhibitors and interleukin-22 (IL-22). Alcoholic liver disease (ALD) is a major cause of chronic liver disease, leading to fibrosis and cirrhosis worldwide. The latest surveillance report published by the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health showed that liver cirrhosis was the 12th leading cause of death in the United States, with a total of 29,925 deaths in 2007, 48% of which were alcohol related (http://pubs.niaaa.nih.gov/ publications/surveillance88/Cirr07.htm). The mechanisms underlying the pathogenesis of ALD are not fully understood. Several major factors contributing the progression of ALD have been proposed 1, 2 and are summarized in Figure 1. Figure 1. Mechanisms underlying the pathogenesis of ALD. Chronic alcohol consumption directly induces hepatocyte death via multiple mechanisms, and indirectly causes hepatocellular damage via the activation of innate immunity and adaptive immunity. All of these events can lead to liver inflammation with accumulation of neutrophils. Inflammation then further promotes hepatocyte death; however, it also plays an important role in promoting liver regeneration. In addition, activation of several innate immunity components (such as TNF-α and complements) contributes significantly to the liver repair. Despite the significant progress on the understanding of ALD pathogenesis, no targeted therapies are available. The cornerstone of treatment for alcoholic hepatitis remains as it was 40 years ago: abstinence, nutritional support, and corticosteroids. The clinical results from the steroid treatment of alcoholic hepatitis have been controversial. Accumulated data indicate that steroid treatment can improve the short-term survival rate in some patients with severe alcoholic hepatitis. The disappointing results from the anti-inflammatory therapy of steroids may be due to several reasons. First, the broad inhibition of inflammation by steroids may not only abolish the inflammation-mediated liver injury but also diminish the inflammation-mediated liver repair. Second, inflammation may not be the major or the only factor contributing to hepatocellular damage in ALD patients. Third, steroid treatment also increases the risk of bacterial infection. 148 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Recently translational studies of human liver samples and animal models have identified several novel therapeutic targets.1, 2 These include targets that can be used to block liver inflammation in ALD, and targets that can be used to promote hepatocyte survival and proliferation. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 149 Figure 2 summarizes the STAT3 signaling activated by various cytokines in hepatocytes. THE TARGETS THAT CAN BE USED TO BLOCK LIVER INFLAMMATION IN ALD: CXC chemokines: The CXC family of chemokines includes IL-8 and Gro-α; these usually attract neutrophils, which infiltrate livers of patients with ALD. In patients with AH, hepatic expression of CXC chemokines is increased and correlates with survival time and the degree of portal hypertension. Reagents that target CXC chemokines might be developed as therapeutics for AH. Gut microbiota and LPS pathway: Modulation of the gut microbiota and LPS pathways might also be used to treat patients with ALD. The gut microbiota and LPS signaling can be modified by probiotics and TLR4 antagonists, respectively, with the latter being proposed as therapeutic agents for the treatment of chronic liver diseases, including ALD. Results from a placebo-controlled trial recently showed that the nonabsorbable antibiotic rifaximin, which modifies the gut microbiota, protected patients from hepatic encephalopathy. Reagents that alter the gut microbiota might also prevent ALD, so further studies are required. Complement: Activation of complement is an important step in the development of ethanol-induced liver injury in mice. Therapeutic interventions to either block complement activation or increase the activity of negative regulators of complement might be used to treat patients with ALD. Several compounds that inhibit complement activation are in phase 1 or 2 trials for the treatment of age-related macular degeneration. These drugs may be developed to treat patients with ALD. Osteopontin: Osteopontin is an extracellular matrix protein that is markedly up-regulated in patients with ALD. The basal expression levels of osteopontin correlate with disease severity (R. Bataller et al, unpublished data, September 2011), indicating that osteopontin contributes to the pathogenesis of ALD. Blockade of osteopontin might be effective for amelioration of ALD. THE TARGETS THAT CAN BE USED TO PROMOTE HEPATOCYTE SURVIVAL AND PROLIFERATION IN ALD: Apoptosis inhibitors: Apoptosis is a prominent feature of chronic liver disease, so apoptosis inhibitors have been investigated in animal models of liver injury and patients with chronic liver diseases. Multiple clinical trials have shown that various caspase inhibitors reduced liver injury and fibrosis in patients with chronic HCV infection or nonalcoholic steatohepatitis.156 ALD is also associated with significant levels of hepatocyte apoptosis, so inhibitors might be a treatment option for ALD. Interleukin-22 (IL-22): IL-22 is a recently discovered hepatoprotective cytokine and seems to have many beneficial effects for the treatment of ALD. IL-22 was originally identified as an IL-9-induced gene and belongs to IL-10 family, but IL-22 and IL-10 have very different biological functions. In contrast, IL-22 has very similar hepatoprotective functions as IL-6 via the activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. Figure 2: STAT3 signaling in hepatocytes. Hepatocytes express high levels of gp130, which is a common signal chain for IL-6 and IL-6 family cytokines, high levels of IL-6 receptors and various corresponding receptors for IL-6 family cytokines. IL-6 family cytokines include leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), cardiotrophin-1 (CT-1), and IL-11. The ligation of these cytokines (IL-6 and IL-6 family cytokines) with their corresponding receptors leads to the dimerization of gp130, followed by dimerization of gp130-associated Janus kinases (JAKs) and phosphorylation of JAKs and gp130. This receptor-kinase complex then recruits and phosphorylates cytoplasmic protein STAT3. Phosphorylated STAT3 forms a dimer, translocates into the nuclei and subsequently induces transcription of many genes. Hepatocytes also express high levels of IL-22R1 and IL-10R2 for IL-22 signaling. IL-6, IL-6 family cytokines, and IL-22 predominantly activate STAT3, but also induce a weak activation of other STATs and MAP kinases. Human hepatocytes express high levels of IFNAR1 and functional IFNAR2c. IFN-α/β predominately induces STAT1 activation in primary human hepatocytes but also induces strong STAT3 activation. Activated STAT3 induces transcription of many genes that play important roles in inducing acute phase responses, promoting hepatocyte survival and liver regeneration, and ameliorating fatty liver. (Wang H., Lafdil F., Kong, X., and Gao, B.: International Journal of Biological Sciences 2011,7:536-550) In 2004, we demonstrated for the first time that IL-22 is a critical survival factor for hepatocytes and plays a key role in protecting against Con A-induced T cell hepatitis.3 The hepatoprotetion of IL-22 in T cell hepatitis was further confirmed using IL-22-deficient mice 4 and IL-22 transgenic mice.5 In addition, IL-22 ameliorates steatosis and hepatocellular damage in many other models of liver injury, including high fat diet-induced fatty liver 6 and acute and chronic alcoholic liver injury.7, 8 The hepatoprotective effect of IL-22 in alcoholic liver injury is likely mediated via the activation of STAT3, followed by the upregulation of anti-apoptotic genes (e.g., Bcl-2 and BcI-xL), anti-oxidative genes (e.g., metallothioneins 1 and 2), and the downregulation of lipogenic genes (e.g., SREBP-1c) in hepatocytes (Fig. 3). 150 POSTGRADUATE COURSE SYLLABUS BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE THE INTERNATIONAL LIVER CONGRESSTM 2012 151 NOTES CLINICAL CASE: LONG-TERM MANAGEMENT OF ALD A. De Gottardi Bern, Switzerland N. Goossens Geneva, Switzerland E-mail: [email protected] A 48 year old man with chronic HCV infection, genotype 1b and cirrhosis (Child-Pugh B 7, MELD 14) comes for a routine visit to your outpatient clinic. Figure 3: The mechanisms underlying the hepatoprotective and antimicrobial effects of IL-22. Treatment of hepatocytes with IL-22 results in upregulation of many genes that prevent hepatocyte apoptosis and stimulate hepatocyte proliferation. IL-22 also downregulates lipogenic genes such as SREBP-1 in the liver, thereby ameliorating fatty liver disease. Finally, IL-22 stimulates hepatocytes to produce lipocalin-2, which may contribute to IL-22 inhibition of bacterial infection. In summary, IL-22 treatment appears to have multiple beneficial effects on alcoholic hepatitis, such as preventing hepatocellular damage, promoting hepatocyte proliferation, and inhibiting bacterial infection. In addition, the side effect of clinical treatment with IL-22 may be minimal because IL-22 only targets epithelial cells such as hepatocytes. Clinical trials examining combination therapy with IL-22 or IL-22 plus corticosteroids for patients with severe alcoholic hepatitis are warranted. REFERENCES Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 2011;141:1572-85. Lucey M, Mathurin P, Morgan T. Alcoholic hepatitis. N Engl J Med 2009, 360: 2758–2769. Radaeva S, Sun R, Pan HN, Hong F, Gao B. Interleukin 22 (IL-22) plays a protective role in T cell-mediated murine hepatitis: IL-22 is a survival factor for hepatocytes via STAT3 activation. Hepatology 2004;39:1332-42. Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Karow M, Flavell RA. Interleukin-22 but not interleukin-17 provides protection to hepatocytes during acute liver inflammation. Immunity 2007;27:647-59. Park O, Wang H, Weng H, Feigenbaum L, Li H, Yin S, Ki SH, Yoo SH, Dooley S, Wang FS, Young HA, Gao B. In vivo consequences of liver-specific interleukin-22 expression in mice: Implications for human liver disease progression. Hepatology 2011;54:252-61. Yang L, Zhang Y, Wang L, Fan F, Zhu L, Li Z, Ruan X, Huang H, Wang Z, Huang Z, Huang Y, Yan X, Chen Y. Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22. J Hepatol 2010;53:339-47. Ki SH, Park O, Zheng M, Morales-Ibanez O, Kolls JK, Bataller R, Gao B. Interleukin-22 treatment ameliorates alcoholic liver injury in a murine model of chronic-binge ethanol feeding: role of signal transducer and activator of transcription 3. Hepatology 2010;52:1291-300. Xing WW, Zou MJ, Liu S, Xu T, Wang JX, Xu DG. Interleukin-22 protects against acute alcohol- induced hepatotoxicity in mice. Biosci Biotechnol Biochem 2011;75:1290-4. He was treated for alcoholic hepatitis 5 years ago and after this episode he continued to drink excessively. After an inpatient treatment for alcoholism, he stopped his alcohol intake 6 months ago. Currently he drinks 3 alcohol-free beers a day. He injected intravenous drugs when he was a teenager and he currently consumes intranasal cocaine once a month. He smokes 20 cigarettes per day. His medication includes losartan, sertralin, propranolol, spironolactone and torasemide. He works as a barkeeper and has a stable family situation. An ultrasound examination with intravenous contrast shows a 3 cm lesion in the right liver with arterial enhancement and washout suggesting hepatocellular carcinoma. There is, in addition, a partial thrombosis of the splenomesenteric confluence. There is no ascites and the spleen is 15 cm in diameter. Laboratory analyses show albumin 31 g/L, bilirubin 32 umol/L (1.87 mg/dL), creatinine 101 umol/L (1.14 mg/dL), INR 1.5, alpha-fetoprotein 20 ug/L. 152 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE STEM CELLS IN ALCOHOLIC LIVER DISEASE: THE ROAD FROM ANIMAL MODELS TO HUMAN STUDIES Laurent Spahr Geneva, Switzerland E-mail: [email protected] Grants: Supported by the Clinical Research Center, University Hospital and Faculty of Medicine, Geneva, the Louis-Jeantet Foundation, and Foundation for Liver and Gut Studies (FLAGS) in Geneva KEY POINTS • The impaired regenerative capacity of alcoholic cirrhosis with ASH (acute-on chronic ALD) participates to the high morbidity and mortality of the disease. • Under specific experimental conditions, animal studies show that bone marrow (BM)-derived stem cells participate in liver regeneration, but mechanisms are incompletely elucidated. • Some benefits derived from BM-derived cell therapy seem associated with the co-administration of G-CSF to mobilize hematopoietic stem cells, produce humoral factors, and facilitate cells homing to the site of injury. • In patients with cirrhosis and ASH, G-CSF stimulates the short-term proliferation of hepatic progenitors. • In patients with decompensated liver disease of mixed aetiology, results of the few RCTs suggest that autologous BM stem cell transplantation is safe and may transiently improve liver function in non alcoholic cirrhosis. • Autologous BM stem cell transplantation in decompensated ALD doesn’t improve liver function (MELD score) over a 3-month period. • Future studies should better characterize the efficiency of G-CSF and BM stem cell therapy in the regeneration and repair of decompensated alcoholic liver, and explore the fate and potential of transplanted cells. INTRODUCTION Cirrhosis is associated with insufficient regeneration in response to injury, due to multiples causes including extensive fibrosis, inflammation, steatosis and replicative senescence of hepatocytes, all of which constitute an unsuitable environment for liver cell proliferation. Acute-on-chronic liver disease is a frequent clinical presentation of ALD, and is associated with a poor outcome. Malnutrition and recent exposure to alcohol have a negative influence on liver cell regeneration by influencing intracellular proliferative pathways. In patients with decompensated ALD and biopsy-proven alcoholic ASH, supportive (N-acetylcystein, calories, vitamins, alcohol abstinence) and anti-inflammatory strategies (corticosteroids) improve short-term survival but overall prognosis remains poor with a 3-month mortality around 25%. Thus, new strategies to stimulate liver regeneration and improve function are needed. As liver transplantation is often not an option at this stage of the disease, a minimally invasive regenerative strategy would be welcome. BONE MARROW CELLS AND LIVER REGENERATION It has been shown that a subpopulation of hepatocytes and cholangiocytes may derive from the bone marrow [1]. Under particular experimental conditions with strong selective pressure (for example immunodeficient animals subject to sublethal liver injury followed by bone marrow transplantation, fumarylacetatoacetate hydrolase (FAH) deficiency, exposition to hepatotoxin such as retrorsin or carbon tetrachloride ), hepatocytes of bone marrow origin may participate in liver cell repopulation. However, the precise mechanisms underlying the beneficial effect of this promising approach are still under investigation. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 153 Firstly, bone marrow-derived pluripotent cells include hematopoietic and mesenchymal stem cells, as well as endothelial progenitor cells, and the relative contribution of each of these cellular contingents in liver repair is ill defined. Secondly, there is much controversy concerning the mechanism by which BM-derived stem cells contribute to liver regeneration (cell fusion, transdifferentiation, local stimulation of endogenous liver cell progenitors, production of cytokines and growth factors, remodelling of fibrous tissue). Thirdly, the mechanisms driving these BM-derived stem cells to the site of liver injury probably involves multiple factors, including stromal-derived factor-1 (ie: SDF-1 binding to CXR4 present on HSC surface). Fourthly, the rate of engraftment of these cells in the diseased liver is difficult to determine, and seems to vary according to the experimental model (< 1% to 50%). Finally, whether the administration of G-CSF (to mobilize BM cells and promote growth factors production), is crucial in governing successful tissue repair is not yet determined. Regarding safety, the small size of BM stem cells avoids them to be trapped within the sinusoids with the potential risk of aggregation, ischemia, and increased portal pressure, but there are some concerns about the risk of inducing cancer (particularly in culture-expanded cells) and the promotion of fibrosis (due to the presence of myofibroblasts among BM cells). IS BM CELLS MOBILIZATION USING G-CSF ASSOCIATED WITH LIVER REGENERATION? Experimental studies Animals exposed to various, severe, often sublethal liver injury (but not related to alcohol) have demonstrated an improved survival and less severe histological lesions when G-CSF was co-administered [2]. In a combined toxic liver injury and partial hepatectomy model, G-CSF induced a strong proliferative activity of oval cells (the intrahepatic progenitors), as well as the generation of a subpopulation of hepatocytes originating in the bone marrow [3]. Thus, G-CSF seems to improve liver regeneration via both direct (the liver stem cell niche) and indirect (contribution to the generation of bone marrow-derived hepatocytes) mechanisms. It has also been suggested that G-CSF may contribute to the homing of bone marrow cells to the injured liver. Clinical studies Transposition of experimental data with G-CSF into clinical studies with cirrhotics is challenging, with regard to tolerance (musculoskeletal pain, fever, allergic reactions) and potentially severe side effects (rare cases of splenic rupture). In a small uncontrolled pilot study [4] on advanced cirrhosis (Child-Pugh > 9) of mixed aetiology, subcutaneous administration of G-CSF (5 ug/kg twice a day for 3 days) was associated with increased circulating levels of CD34+ mobilized BM cells. Tolerance was excellent, although transient increase in spleen size was reported during treatment. These results were confirmed in a larger group of patients with acute decompensated cirrhosis, using either a 5 ug/kg/day or a 15 ug/kg/day dose for 5 days, and increased circulating CD34+ cells were associated with a production of stromal cell derived factor (SDF-1), a potent chemo attractant of hematopoietic progenitor cells, as well as the growth factor VEGF [5]. However, these biological effects didn’t translate into clinical improvement over a 3-week period. To further explore the role of G-CSF in decompensated cirrhosis, we performed a randomized trial to study the shortterm effect on liver regeneration in patients with decompensated ALD and superimposed ASH (median Child-Pugh score of 10) [6]. Using a 5-day course of 10 ug/kg/day G-CSF treatment, circulating CD34+ hematopoietic stem cells were detectable in G-CSF treated patients, but the number of CD34+ cells was lower than the value obtained in healthy stem cells donors. Using a double immunostaining methods for the proliferation marker MiB1 and cytokeratin 7 and 18 (immunoreactivity for hepatic progenitors and mature hepatocyte, respectively) performed on baseline and a repeat liver biopsy at day 7, we demonstrated a significant increase in MiB1+/CK7+ and MiB1+/CK18+ hepatic cells in liver biopsy specimen limited to G-CSF-treated patients. In addition, changes in circulating CD34+ and MiB1+/CK7+ in liver tissue between baseline and day-7 values showed a positive correlation (r = 0.65, p < 0.03). Again, these encouraging results on liver cell proliferation were not associated with any benefits in terms of liver function over a 4-week study period. 154 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 Figure: evolution of the number of proliferating hepatic progenitors (MiB1+/CK7+ cells) and mature hepatocytes (MiB1+/CK18+ cells), expressed as % changes in the liver biopsy repeated at day 7 in both G-CSF treated and non treated patients with cirrhosis and ASH [6] Harb (2009) Taken together, G-CSF administration in patients with cirrhosis is well tolerated, is associated with signs of BM derived cell mobilization, and stimulates the proliferation of hepatic progenitors on the short term in decompensated alcoholics. However, no improvement in liver function was evident over a 4-week period. Li (2010) THE INTERNATIONAL LIVER CONGRESSTM 2012 Monocrotaline + radiation in rats No G-CSF 5 x 106 unsorted BM Cells Tail vein G-CSF + 105 CD34+ cells Tail vein Radiation injury in mice 155 Improved liver repair via SEC of BM origin Improved liver repair Abbreviation: SEC: sinusoidal endothelial cell; NOD-SCID: non obese diabetic severe combined immunodeficiency IS G-CSF FOLLOWED BY BM STEM CELL TRANSPLANTATION ASSOCIATED WITH LIVER REGENERATION? Experimental studies Transplantation of bone marrow derived cells (either hematopoietic, mesenchymal, or endothelial progenitors) may contribute to liver repair in acute liver injury models [7] [8] [9] [10]. Due to great variability between studies (design, type of liver injury, use of G-CSF, protocols for cellular isolation and characterization, etc..) and real life situations (fibrosis, repeated episodes of liver injury, bone marrow exhaustion, etc..), results should be interpreted with caution. Table 1: Selected list of experimental studies of bone marrow derived cells transplantation Author (yr) Model Transplantation protocol No G-CSF Terai (2003) CCl4 in mice Route Tail vein 105 unsorted BM Cells Kuo (2008) Piscaglia (2007) CCl4 in NOD-SCID No G-CSF mice 1.4 x 106 MSC/kg Radiation injury in rats G-CSF + 5 x 107 unsorted BM Cells Intravenous Table 2: Selected list of uncontrolled clinical studies of autologous BM- derived cells transplantation in chronic liver disease Author (yr) Pts (n) Clinical setting Evidence of transdifferentiation 25% repopulation of damaged liver Stimulation of endogenous hepatocyte proliferation stimulation Improved liver repair Protocol Route Outcome Peripheral vein Improved Child-Pugh score at 6 months PV = 3 HA = 2 Modest improvement in biological parameters No G-CSF BMA+ 3 x 106 CD34+ cells HA Major side effect G-CSF + No BMA 2 x 108 MNC HA Child-Pugh score at 3 No G-CSF Terai (2006) 9 Viral compensated BMA+ cirrhosis 78 x 109 MNC Outcome Endogenous oval cell Tail vein Clinical studies Clinical studies with autologous BM derived stem cells have reported some benefits in terms of biological and clinical parameters (serum bilirubin, albumin, coagulopathy, ascites), but the vast majority are uncontrolled and only few recent trials have included a control group [11] [12-14]. To optimize the potential benefit of BM-derived pluripotent cells, unsorted mononuclear cells (including both hematopoietic and mesenchymal stem cells) are used. Table 3 summarizes the results issued from 3 RCT[15-17]. In a Chinese study of decompensated hepatitis B patients[17] (mean MELD score of 30; mean number of BM cells 3.4 x 10e8), a significant improvement in MELD score was observed during several weeks after treatment, while autologous BM transplant in decompensated alcoholics (mean MELD score of 19; mean number of BM cells/kg: 10e8) was not associated with any benefits in terms of liver function over 3 months of follow-up[16]. Thus, autologous BM stem cell therapy seems relatively well tolerated without severe side effects, and is associated with either a modest and transient improvement in liver function or with no benefit as compared to standard of care alone. Cirrhosis Gordon (2006) 5 (4 = alcoholic) G-CSF+ No BMA 106-108 CD34+ cells Mohamadnejad (2007) Pai (2008) 4 9 Decompensated cirrhosis (mixed etiology) Abstinent alcoholic cirrhosis Improvement in months 156 POSTGRADUATE COURSE SYLLABUS Table 3 : Controlled clinical studies of autologous BM- derived cells transplantation in chronic liver disease Author (yr) Lyra (2010) Patients (n) Clinical setting 15 Cirrhosis on LT list Protocol No G-CSF BMA+ Route Outcome HA Transient improvement in bilirubin HA Transient improvement in MELD score HA No benefit No G-CSF Peng (2011) Spahr (2011) 53 28 Decompensated BMA+ chronic Hep B 3.4 x 108 MNC Decompensated alcoholic liver disease BARCELONA . SPAIN APRIL 18 - 19/2012 ALCOHOLIC LIVER DISEASE G-CSF + BMA+ 0.47 x 108 MNC/k Abbreviation: BMA: bone marrow aspiration; MNC: mononuclear cells; HA: hepatic artery; PV: portal vein CONCLUSIONS AND PERSPECTIVES BM stem cell therapy offers the potential for a novel approach to liver regeneration. Based on available data, the contribution of BM-derived stem cells to liver repair seems marginal, and the mechanisms are incompletely understood. RCTs in patients with decompensated liver disease suggest that autologous BMC transplantation is safe and may transiently improve clinical and biological parameters. The aetiology of liver disease may account for differences in the response to stem cell therapy, as patients with decompensated ALD don’t derive any benefits in terms of liver function compared to standard of care treatment. Future studies should better characterize the efficiency of G-CSF and BM stem cell therapy in the regeneration/ repair mechanisms of the injured alcoholic liver, and explore the fate and potential of transplanted cells. Figure: evolution of the MELD score in patients with decompensated ALD (n=58) (ref 21) THE INTERNATIONAL LIVER CONGRESSTM 2012 157 Abbreviations: BM: bone marrow; ALD: alcoholic liver disease; ASH: alcoholic steatohepatitis; G-CSF: granulocyte colony-stimulating factor; RCT: randomized controlled trial REFERENCES Theise, N.D., et al., Liver from bone marrow in humans. Hepatology, 2000. 32(1): p. 11-6. Yannaki, E., et al., G-CSF-primed hematopoietic stem cells or G-CSF per se accelerate recovery and improve survival after liver injury, predominantly by promoting endogenous repair programs. Experimental hematology, 2005. 33(1): p. 108-19. Piscaglia, A.C., et al., Granulocyte-colony stimulating factor promotes liver repair and induces oval cell migration and proliferation in rats. Gastroenterology, 2007. 133(2): p. 619-31. Gaia, S., et al., Feasibility and safety of G-CSF administration to induce bone marrow-derived cells mobilization in patients with end stage liver disease. Journal of hepatology, 2006. 45(1): p. 13-9. Di Campli, C., et al., Safety and efficacy profile of G-CSF therapy in patients with acute on chronic liver failure. Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, 2007. 39(12): p. 1071-6. Spahr, L., et al., Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial. Hepatology, 2008. 48(1): p. 221-9. Terai, S., et al., An in vivo model for monitoring trans-differentiation of bone marrow cells into functional hepatocytes. Journal of biochemistry, 2003. 134(4): p. 551-8. Kuo, T.K., et al., Stem cell therapy for liver disease: parameters governing the success of using bone marrow mesenchymal stem cells. Gastroenterology, 2008. 134(7): p. 2111-21, 2121 e1-3. Harb, R., et al., Bone marrow progenitor cells repair rat hepatic sinusoidal endothelial cells after liver injury. Gastroenterology, 2009. 137(2): p. 704-12. Li, N., et al., Human CD34+ cells mobilized by granulocyte colony-stimulating factor ameliorate radiation-induced liver damage in mice. Stem cell research & therapy, 2010. 1(3): p. 22. Terai, S., et al., Improved liver function in patients with liver cirrhosis after autologous bone marrow cell infusion therapy. Stem cells, 2006. 24(10): p. 2292-8. Gordon, M.Y., et al., Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. Stem cells, 2006. 24(7): p. 1822-30. Mohamadnejad, M., et al., Phase 1 human trial of autologous bone marrow-hematopoietic stem cell transplantation in patients with decompensated cirrhosis. World journal of gastroenterology : WJG, 2007. 13(24): p. 3359-63. Pai, M., et al., Autologous infusion of expanded mobilized adult bone marrow-derived CD34+ cells into patients with alcoholic liver cirrhosis. The American journal of gastroenterology, 2008. 103(8): p. 1952-8. Lyra, A.C., et al., Infusion of autologous bone marrow mononuclear cells through hepatic artery results in a short-term improvement of liver function in patients with chronic liver disease: a pilot randomized controlled study. European journal of gastroenterology & hepatology, 2010. 22(1): p. 33-42. Spahr, L. et al. Autologous bone marrow stem cell transplantation versus standard of care in patients with decompensated alcoholic liver disease. Hepatology, 2011. 54(S1): p. A62. Peng, L., et al., Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: Short-term and long-term outcomes. Hepatology, 2011. 158 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 159 CURRENT POLICIES TO REDUCE THE HARM DONE BY ALCOHOL Peter Anderson Newcastle upon Tyne, UK E-mail: [email protected] KEY POINTS • A substantive evidence base of systematic reviews and meta-analyses inform effective alcohol policy. • Making alcohol more expensive and less available are highly cost-effective strategies to reduce harm. • Banning alcohol advertising and drink driving counter measures are also cost-effective. • Individually directed interventions to already at risk drinkers are cost-effective and should be widely implemented. • School-based education does not reduce harm, but public information and education programmes can increase attention to alcohol on public and political agendas. HARM DONE BY ALCOHOL Both the volume of lifetime alcohol use and a combination of frequency of drinking and amount drunk per drinking occasion increase the risk of alcohol-related harm, largely in a dose-dependent manner. Surrogate and illegal alcohols can bring an extra health risk from high ethanol levels and toxic contaminants, such as methanol and lead, often compounded by social marginalization. Alcohol is an intoxicant affecting a wide range of structures and processes in the central nervous system which, interacting with personality characteristics, associated behaviour and sociocultural expectations, are causal factors for intentional and unintentional injuries and harm to people other than the drinker, including interpersonal violence, suicide, homicide, crime and drink-driving fatalities, and a contributory factor for risky sexual behaviour, sexually transmitted diseases and HIV infection. Alcohol is a potent teratogen with a range of negative outcomes to the foetus, including low birth weight, cognitive deficiencies and foetal alcohol disorders. Alcohol is neurotoxic to brain development, leading in adolescence to structural hippocampal changes and, in middle age, to reduced brain volume. Alcohol is a dependence-producing drug, similar to other substances under international control, through its reinforcing properties and neuroadaptation in the brain. Alcohol is hepatotoxic, causing between 75% and 80% of all liver cirrhosis in Europe; this is attributed to a relatively low prevalence of other risk factors for this disease in Europe, and, as a consequence, trends in liver cirrhosis mortality rates follow closely trends in alcohol consumption. Alcohol is an immunosuppressant, increasing the risk of communicable diseases, including tuberculosis. Alcoholic beverages are classified as a carcinogen by the International Agency for Research on Cancer, increasing the risk of cancers of the oral cavity and pharynx, oesophagus, stomach, colon, rectum and breast in a linear dose–response relationship. Alcohol has a bi-form relationship with coronary heart disease. In low and apparently regular doses, it appears to be cardio-protective, but at high doses, particularly when consumed in an irregular fashion, it is cardio-toxic. The lifetime risk of dying form an alcohol-related injury across the total European population over 15 years old increases exponentially with increasing daily alcohol consumption beyond 10g alcohol per day, the first data point, Figure 1. At any given level of alcohol consumption, the risks are much higher for men than for women. Figure 1 Absolute annual risk of death from alcohol-related diseases, European Region of WHO. The WHO European Region has the highest proportion of total ill health and premature deaths due to alcohol in the world, as measured by disability adjusted life years (DALYs), where one DALY is a year of ill-health or premature death, measuring a gap between present health status and what could best be achieved. Eighteen per cent and 5% of all female of all male ill-health and premature death is due to alcohol (world average, 7% and 1% respectively). The social cost of alcohol to the WHO European Region as a whole is not known. However, based on the results of 21 European studies, the total tangible cost of alcohol to the European Union as it existed in 2003, was estimated to be €125 billion (range of estimates: €79–220 billion), equivalent to 1.3% of gross domestic product (0.9–2.4%). Actual spending on alcoholrelated problems accounts for €66 billion of this, while potential production not realized due to absenteeism, unemployment and premature mortality accounts for a further €59 billion. There are enormous differences in life expectancy between different parts of Europe, and this has been most comprehensively studied in the European Union, where, about 25% of the difference in life expectancy between western and eastern Europe for men aged 20–64 years in 2002 is attributed to alcohol, largely as a result of differences in heavy episodic drinking patterns, and deaths from cardiovascular diseases and injuries. EFFECTIVE POLICIES TO REDUCE THE HARM DONE BY ALCOHOL A summary of the estimated cost and impact of different interventions, compared to a Europe with none of these policies is shown in Table 1, with an estimate of the cost per DALY saved. Pricing policies Drinkers respond to changes in the price of alcohol as they do to changes in the prices of other consumer products. When other factors are held constant, such as income and the price of other goods, a rise in alcohol prices leads to less alcohol consumption and less alcohol-related harm, and vice versa. Given that demand for alcohol is usually found to be relatively inelastic to price, increasing alcohol taxes not only reduces alcohol consumption and related harm but increases government revenue at the same time, noting that in general, alcohol taxes are well below their maximum revenue-producing potential and that the revenue collected is usually well below the social costs of alcohol. Beverage elasticities are generally lower for the preferred beverage in a particular market and tend to decrease with higher levels of consumption. Controlling for overall consumption, beverage preferences and time period, consumer responses to changes 160 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 161 in the price of alcoholic beverages are found not to vary by country. Policies that increase alcohol prices delay the time when young people start to drink, slow their progression towards drinking larger amounts, and reduce their heavy drinking and the volume of alcohol drunk on each occasion. Price increases reduce the harm caused by alcohol, which is an indicator that heavier drinking has been reduced. Setting a minimum price per gram of alcohol can be as effective as an across-the-board tax increase, with both options increasing the cost to heavy consumers far in excess of the cost to light consumers. Natural experiments in Europe consequent to economic treaties have shown that as alcohol taxes and prices have been lowered, so sales and alcohol consumption have usually increased. Table 1 shows that tax increases (of 20% or even 50%) are highly cost-effective throughout Europe. Even accounting for longer life, and thus potentially increased social welfare costs, taxation remains a highly cost-effective alcohol policy option. As discussed above, the effect of alcohol tax increases could be mitigated by illegal production, tax evasion and illegal trading, which accounts for approximately 12% of all consumption in Eur-A countries and 40% in Eur-B and Eur-C countries. Reducing this unrecorded consumption (by 20–50%) via concerted tax enforcement efforts is estimated to cost 50–100% more than a tax increase but produces similar levels of effect. In settings with higher levels of unrecorded production and consumption, increasing the proportion of consumption that is taxed (and therefore more costly to the price-sensitive consumer) may represent a more effective pricing policy than a simple increase in excise tax, which may only encourage further illegal production, smuggling and cross-border purchases. Table 1 Costs, impact and cost-effectiveness of different policy options in Europe a) Implementation cost in 2005 international dollars (millions). b) Cost–effectiveness ratio, expressed in terms of international dollars per DALY saved. c) Not applicable because the effect size is not significantly different from zero (the cost–effectiveness ratio would therefore approach infinity). MARKETING OF ALCOHOLIC BEVERAGES Despite their methodological difficulties, econometric studies of the link between alcohol advertising and consumption have found effects of alcohol advertising on behaviour, although not across all studies. The strongest evidence comes from longitudinal studies that have shown an impact of various forms of alcohol marketing, including exposure to alcohol advertising in the traditional media as well as promotion in the contents of films and via alcohol-branded merchandise, on when young people start to drink and on riskier patterns of drinking by young people. The effects of exposure seem to be cumulative; in markets where alcohol is more widely advertised young people are more likely to continue to increase their drinking as they move into their mid-twenties, whereas drinking declines at an earlier age among those who are less exposed. These findings of the impact that advertising can have on young people’s behaviour are supported by experimental studies, and are in keeping with research on young people’s smoking and children’s food preferences. In some jurisdictions, alcohol marketing relies on self-regulation by economic operators, including in advertising, the media and by alcohol producers. Evidence from a number of studies shows that these voluntary systems do not, however, prevent the kind of marketing that has an impact on younger people. It should be noted that a total marketing strategy is multilevel, including not only marketing and promotional activities but also product development, pricing, physical availability, and market segmentation and targeting. Further, while alcohol is marketed through increasingly sophisticated advertising in the 162 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE mainstream media, it is also promoted by linking alcohol brands to sports and cultural activities through sponsorships and product placements, and by direct marketing using new technologies such as the internet, podcasting and mobile telephones. ADDRESSING THE AVAILABILITY OF ALCOHOL Government monopolies on the sale of alcohol can reduce alcohol-related harm. Such systems tend to have fewer outlets open for shorter hours than private retailers. A licensing system for the sale of alcohol allows for control, since infringement of the laws can be punished by revocation of the licence. On the other hand, a licensing system with fees generated from licences can lead to a proliferation of licensed establishments as an income-generating mechanism for jurisdictions. The implementation of laws setting a minimum age for the purchase of alcohol shows clear reductions in drink-driving casualties and other alcohol-related harms. The most effective means of enforcement is on sellers, who have a vested interest in retaining the right to sell alcohol. In general, the number of alcohol outlets is related to the level of alcohol-related harm, which is strongest when there are major changes in the number or type of such outlets. A greater density of alcohol outlets is associated with higher alcohol consumption among young people, with increased levels of assault and with other harms such as homicide, child abuse and neglect, self-inflicted injury and, with less consistent evidence, road traffic accidents. While extending the times of sale can redistribute the times when many alcohol-related incidents occur, such extensions generally do not reduce the rates of violent incidents and often lead to an overall increase in consumption with association problems. Reducing the hours or days of sale of alcoholic beverages leads to fewer alcohol-related problems, including homicides and assaults. Strict restrictions on availability can create an opportunity for a parallel illicit market, although in the absence of substantial home or illicit production, this can in most circumstances be managed with enforcement. Where a large illicit market exists, licence-enforced restrictions may increase the competitiveness of the alternative market, and this will need to be taken into account in policy-making. DRINK-DRIVING POLICIES AND COUNTERMEASURES The setting of a legal blood alcohol concentration (BAC) level for driving and lowering it is effective in reducing drink-driving casualties. Intensive random breath-testing, where police regularly stop drivers on a random basis to check their BAC level, and checkpoints where all cars are stopped and drivers suspected of drink-driving are breath-tested, do reduce alcohol-related injuries and fatalities. There is evidence for some effectiveness in setting lower BAC levels, including a zero level, for young or novice drivers, administrative suspension of the driver’s licence for a driver caught with a positive BAC level, and mandatory treatment and the use of an ignition interlock (a mechanical device which does not allow a car to be driven by a driver with a BAC above a low level) for repeat drink-drivers. In contrast, there is evidence that designated driver schemes have no effect. RESPONSE OF THE HEALTH SECTOR There is a clear gap in the potential contribution of the health sector’s response in reducing the harm done by alcohol. In primary health care settings, commonly less than 10% of the population at risk of becoming hazardous and harmful drinkers are identified and less than 5% of those who could benefit are offered brief interventions. A 2004 needs assessment study in England found that only 1 in 18 (5.6%) of alcoholdependent drinkers actually accessed treatment each year, with regional variations ranging from 1 in 102 to 1 in 12. The health sector workforce in Europe is an enormous resource with great potential. Disorders related to alcohol use are included as mental and behavioural disorders within the ICD-10 classification of mental and behavioural disorders, and there is a legal imperative to provide help and treatment for alcohol use disorders. Brief advice heads the list of effective and cost-effective evidence-based treatment methods. Much is now also understood about the mechanisms for implementing brief advice programmes countrywide. For individuals with more severe alcohol dependence and related problems, a wide variety of specialized treatment approaches have been evaluated with evidence for their effectiveness for behavioural and pharmacological therapies. Table 1 shows that the cost-effectiveness of brief interventions is not as favourable as the population-level policy instruments summarized above, because they require direct contact with health care professionals and services. Although brief interventions are the most expensive to implement, it should be noted that within health service expenditure, brief interventions for hazardous and BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 163 harmful alcohol consumption are one of the most cost-effective of all health service interventions in leading to health gain. RAISING AWARENESS While the provision of information and education is important to raise awareness and impart knowledge, by themselves information and education do not lead to sustained changes in alcohol-related behaviour. Education can, however, be a tool for awareness and raising support, and an important feature of a broader alcohol strategy. Campaigns and health education messages funded by the alcohol industry seem to have negative effects, serving to advance the interests of both the industry’s sales and public relations. Although warning labels have little impact on behaviour, they are important in helping to establish a social understanding that alcohol is a special and hazardous commodity. OVERVIEW OF EFFECTIVE POLICIES TO REDUCE THE HARM DONE BY ALCOHOL Essentially, those policies that regulate the environment in which alcohol is marketed (economic and physical availability) are effective in reducing alcohol-related harm, Table 2. Enforced legislative measures to reduce drinking and driving are effective, as are individually-directed interventions to already at-risk drinkers. On the contrary, the evidence shows that information and education-type programmes do not reduce alcoholrelated harm, although they have a role in providing information, reframing alcohol-related problems, and increasing attention to and acceptance of alcohol on the political and public agendas. Table 2 Summary of the evidence of the effectiveness of alcohol policies POSTGRADUATE COURSE SYLLABUS 164 ALCOHOLIC LIVER DISEASE REFERENCES Anderson P, Baumberg B. Alcohol in Europe. London, Institute of Alcohol Studies, 2006 (http://ec.europa.eu/health/ph_determinants/life_style/alcohol/documents/alcohol_europe.pdf. Accessed 30 June 2009). Rehm, J, Mathers, C, Popova, S, Thavorncharoensap, M, Teerawattananon, Y, Patra, J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol use disorders. Lancet 2009; 373(9682): 2223-2233. Anderson P, Chisholm D, Fuhr DC. Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol. Lancet 2009; 373: 2234–46. Anderson, P. Evidence for the effectiveness and cost-effectiveness of interventions to reduce alcohol-related harm. Copenhagen, World Health Organization Regional Office for Europe, 2009. Babor T, Caetano R, Casswell S, Edwards G, Giesbrecht N, Graham K, et al. Alcohol: No ordinary commodity (Second Edition). Oxford, Oxford University Press, 2010. Casswell S, Thamarangsi T. Reducing the harm from alcohol: call to action. Lancet 2009; 373: 2247–57. Gordon, R. & Anderson, P. Science and alcohol policy: A case study of the EU Strategy on Alcohol. Addiction 2011 106 Supplement 55-66. Rehm J, Anderson P, Kanteres F, Parry CD, Samokhvalov AV, & Patra J. Alcohol, social development and infectious disease. 978-1-77052-444-6. Toronto, ON: Centre for Addiction and Mental Health, 2009 Rehm J, Baliunas D, Borges GLG, Graham K, Irving HM, et al. The relation between different dimensions of alcohol consumption and burden of disease - an overview. Addiction 2010; 105: 817-843 World Health Organization. Handbook for action to reduce alcohol-related harm. Copenhagen, World Health Organization Regional Office for Europe, 2009. BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 165 ILLEGALLY PRODUCED SPIRITS IN EASTERN EUROPE: TO WHAT EXTENT AND AT WHAT RISK? Dirk W. Lachenmeier Karlruhe, Germany E-Mail: [email protected] KEY POINTS • Unrecorded alcohol comprises homemade, illegally produced, or smuggled alcohol products as well as surrogate alcohol that is not officially intended for human consumption (e.g., mouthwash, perfumes and eau-de-colognes). • Unrecorded alcohol consumption is highest in Eastern Europe. • Illegally produced spirits are often sold at higher alcoholic strength (>45% vol) but for half the price of legal beverages, potentially leading to more detrimental patterns of drinking and overproportional rates of liver cirrhosis. • There is currently a lack of data to demonstrate causality between the quality of illicit spirits (e.g., higher levels of certain contaminants in home-produced products) and liver toxicity on a population scale. • Polyhexamethyleneguanidine (PHMG) contained in surrogate alcohol (antiseptic liquids) from Russia was associated with an outbreak of acute cholestatic liver injury, histologically different from conventional alcoholic liver disease. INTRODUCTION In Central and Eastern Europe, large discrepancies can be found between recorded alcoholic beverage consumption and alcohol-related mortality (1). One example is Hungary, where mortality from liver disease is approximately fourfold that of countries with similar per capita consumption of alcohol (e.g. (2, 3)). One reason for this might be the particularly high unrecorded consumption (2). Despite the high levels of unrecorded consumption in some countries (up to 40% of total consumption), there are almost no data on long-term consequences, such as chronic diseases, which may stem specifically from unrecorded consumption. This is partially due to the fact that few people consume only unrecorded alcohol over time (4). Consider the example of a person who died of alcoholic liver cirrhosis in Russia, and had been mainly consuming unrecorded alcohol products in his final years. Typically, he would have been drinking only recorded alcohol for some time before switching to surrogate alcohol for economic reasons when drinking became increasingly heavily (5). With this switch and subsequent exposure to ‘other’ forms of alcohol, there are three potential impacts (4): •The alcoholic liver cirrhosis would have taken exactly the same course •The alcoholic liver cirrhosis would have taken a different course, for example, later onset, longer duration, or no fatal outcome, if this person had consumed recorded alcohol only. • The alcoholic liver cirrhosis would not have occurred with consumption of recorded alcohol. It is extremely difficult to determine whether unrecorded consumption or mainly unrecorded consumption is causal in the onset of a chronic disease; i.e., whether the components which differ between recorded and unrecorded alcohol cause certain health consequences (6). As a result, few studies have investigated whether unrecorded consumption causes health consequences over and above those of recorded consumption. Notably, such a study was conducted in India (7), wherein the authors concluded that unrecorded consumption (country liquor) was associated with a general risk of alcoholic liver disease, particularly alcoholic liver cirrhosis, despite having relatively low alcohol concentrations compared with the local recorded type. However, this study was not well controlled, and therefore confounding by social status and other factors cannot be excluded (4). 166 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Figure 1. Comparison of levels of unrecorded alcohol consumption and liver cirrhosis death rates in Europe for 2005 (data from WHO (8); no data available for uncoloured countries) BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 167 Figure 2. Correlation between unrecorded consumption and liver cirrhosis mortality for countries worldwide (own calculation based on WHO data (8); the lower curve shows the result after controlling for heavy episodic drinking). In Figure 1, Hungary and Romania show high levels of unrecorded adult (15+) per capita alcohol consumption (4.0 litres of pure alcohol per year). For these countries, liver cirrhosis rates (47 and 43 per 100,000 adult population for Hungary and Romania, respectively) were much higher than for other European countries (only the Republic of Moldova showed higher liver cirrhosis rates). Comparably low unrecorded alcohol consumption in France, Spain, and Switzerland (0.34, 1.4, and 0.50 litres of pure alcohol per year) were in agreement with liver cirrhosis rates in these countries (less than 12 deaths per 100,000 adult population from alcoholic liver disease). INVESTIGATION INTO THE INFLUENCE OF UNRECORDED ALCOHOL CONSUMPTION ON LIVER CIRRHOSIS MORTALITY To provide further insight into the connection between unrecorded alcohol consumption and liver cirrhosis, the following data was obtained from the WHO Global Information System on Alcohol and Health (GISAH) (8): • The age-standardised death rate (liver cirrhosis), defined as the number of individuals in a given population (100,000 people) who died from alcoholic liver disease during a calendar year (2005). Only adults (population above 15 years) were taken into account. • The levels of unrecorded and total consumption (in litres of pure alcohol) for the year 2005 and for the population older than 15 years. Recorded alcohol consumption refers to official statistics (production, import, export, and sales or taxation data), while unrecorded alcohol consumption refers to alcohol which is not taxed and is outside the usual system of governmental control, such as home- or informally-produced alcohol (legal or illegal), smuggled alcohol, surrogate alcohol (which is alcohol not intended for human consumption), or alcohol obtained through cross-border shopping (which is recorded in a different jurisdiction). The percentage of unrecorded alcohol consumption for each country was then calculated from these data. • Heavy episodic drinkers, defined as the percentage of adults (aged 15+) who have drunk at least 60 grams (approximately 6 standard alcoholic drinks) or more of pure alcohol on at least one occasion weekly. • The data were evaluated using Origin V.7.5 (Originlab, Northampton, USA). Statistical correlation between the investigated parameters was evaluated using linear regression for all countries for which data was available. For all calculations, statistical significance was assumed below the 0.05 probability level. The results are shown in Figure 2. There appears to be a statistically significant correlation between the level of unrecorded consumption and liver cirrhosis mortality (R=0.65, p<0.0001). This trend upholds even after controlling for per capita consumption (R=0.35, p=0.04; for calculation see Ref. (9)), but becomes non-significant after controlling for heavy episodic drinking (R=0.35, p=0.12). However, five countries (Hungary, Estonia, Slovakia, Mauritius, and Ecuador) still showed overproportional liver cirrhosis mortality after the adjustment for heavy episodic drinking. However as consumption of alcohol per se may also cause liver cirrhosis, the specific contribution of unrecorded alcohol is not clear (9, 10). Mechanisms potentially leading to overproportional liver cirrhosis mortality associated with unrecorded consumption It has been suggested that the large differences in cirrhosis mortality rates between Hungary and Romania and the rest of Europe, mentioned above, could be due to the composition of unrecorded alcohol products (2) rather than differences in the volume or patterns of consumption (11, 12). Several studies (see summary in Ref. (10)) have used chemical analysis to characterise the composition of unrecorded alcoholic beverages with focus on potential harmful components (Table 1). If we examine the potential chronic toxic effects that are anecdotally associated with unrecorded consumption (e.g. liver cirrhosis), there is only one consistent finding: unrecorded alcohols often contain higher ethanol concentrations (considerably higher than 40% vol) than recorded alcohols (4). This may also have a detrimental effect, especially for alcohol poisoning and injuries. Due to the lack of labelling on unrecorded alcoholic beverages, the necessity of dilution to drinking strength in most cases might be unknown leading to these beverages being consumed in their original, high alcoholic strength form (10). 168 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE Table 1. Compounds potentially associated with toxicity in unrecorded alcohol BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 169 diethyl phthalate (DEP) (0.08–0.15%) and PHMG (0.10–0.14%). PHMG is an effective antiseptic and is commonly used for suppression of hospital infection in the Russian Federation (16) and DEP denatures alcohol (17). Several other studies detected PHMG together with DEP in disinfectants that were used as an ethanol source in poisoning cases in Russia (6, 16, 18). On the basis of clinical manifestations and laboratory findings of 579 poisoned patients, Ostapenko et al. (15) concluded that the cholestatic hepatitis (histologically different from conventional alcoholic liver disease) was caused by PHMG, while a history of alcohol-induced hepatitis and cirrhosis contributed to a more severe course of the poisoning. Other factors such as DEP or chronic viral hepatitis may have further contributed to multifactorial liver damage. However, little is known about the alcohol consumed, which led to these poisonings, the role of ethanol concentration, drinking patterns, or the role of unrecorded consumption (10, 19). CONCLUSIONS Recent research has shown that concerns about the toxicity of unrecorded alcohol were mostly exaggerated (4). For example, quantitative risk comparisons have shown that the potency of ethanol for liver toxicity is at least 5,000 times greater than that of ethyl carbamate (20). Rather than by reference to alcohol quality, liver cirrhosis rates could be better explained by the higher alcoholic strength of the unrecorded alcohol consumed, problematic drinking patterns, lower socioeconomic status and poor health status and the interaction effect between these factors (4). Acknowledgements The author is grateful for the assistance of Dr. Yulia Monakhova in conducting the statistical analysis. REFERENCES Other components besides ethanol analysed in unrecorded alcohols have not been found in the vast majority of unrecorded alcohol samples at levels known to cause harm to health on a population scale (13). While several of the contaminants detected in unrecorded alcohol (especially copper and ethyl carbamate) could be hepatotoxic above certain thresholds, the typical human exposure is less than 1% of the threshold doses in rodents (13). Therefore, while further research in this area is certainly necessary, it would appear that the volume of alcohol consumption and/or drinking patterns rather than alcohol quality predominantly contribute to the differences in mortality (13). Unrecorded alcohol may contribute to this by the fact that unrecorded alcohol is often higher in strength and its lower price may further contribute to drinking greater quantities (13). METHANOL AND PHMG: EXCEPTIONS TO THE RULE While unrecorded alcohol seldom contains substances more toxic than ethanol itself, the exception to the rule may be isolated outbreaks of methanol poisoning (14) as well as the occurrence of polyhexamethyleneguanidine hydrochloride (PHMG), which was associated with an outbreak of acute cholestatic liver injury in Russia connected to the consumption of surrogate alcohol (15). In that case, the alcohol that was consumed was a liquid intended for indoor disinfection, which contained ethanol (93%), IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Alcohol consumption and ethyl carbamate. IARC Monogr Eval Carcinog Risks Hum 2010;96:1-1428. Szücs S, Sárváry A, McKee M, Ádány R. Could the high level of cirrhosis in central and eastern Europe be due partly to the quality of alcohol consumed? An exploratory investigation. Addiction 2005;100(4):536-542. Rehm J, Sulkowska U, Manczuk M, Boffetta P, Powles J, Popova S, et al. Alcohol accounts for a high proportion of premature mortality in central and eastern Europe. Int J Epidemiol 2007;36(2):458467. Rehm J, Kanteres F, Lachenmeier DW. Unrecorded consumption, quality of alcohol and health consequences. Drug Alcohol Rev 2010;29(4):426-436. Gil A, Polikina O, Koroleva N, McKee M, Tomkins S, Leon DA. Availability and Characteristics of Nonbeverage Alcohols Sold in 17 Russian Cities in 2007. Alcohol Clin Exp Res 2009;33(1):79-85. Solodun YuV, Klevno VA, Lelyukh TD, Maslauskaite LS, Yaverbaum AP, Ermolaeva NB, et al. Forensic-medical evaluation of toxic hepatitis associated with surrogate alcohol poisoning. Sud Med Ekspert 2008;51(4):23-28. Narawane NM, Bhatia S, Abraham P, Sanghani S, Sawant SS. Consumption of ‘country liquor’ and its relation to alcoholic liver disease in Mumbai. J Assoc Physicians India 1998;46(6):510-513. WHO. Global Information System on Alcohol and Health (GISAH). Geneva, Switzerland. www.who. int/globalatlas/default.asp (Accessed 2011-11-30): World Health Organization; 2011. Lachenmeier DW, Taylor BJ, Rehm J. Alcohol under the radar: Do we have policy options regarding unrecorded alcohol? Int J Drug Policy 2011;22(2):153-160. Lachenmeier DW, Gmel G, Rehm J. Unrecorded alcohol consumption. In: Boyle P, Boffetta P, Lowenfels A, Burns H, Brawley O, Zatonski W, et al., editors. Alcohol: Science, policy and public health. Oxford, UK: Oxford University Press; 2012, in press. Popova S, Rehm J, Patra J, Zatonski W. Comparing alcohol consumption in central and eastern Europe to other European countries. Alcohol Alcohol 2007;42(5):465-473. 170 POSTGRADUATE COURSE SYLLABUS ALCOHOLIC LIVER DISEASE BARCELONA . SPAIN APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESSTM 2012 171 WHO Regional Office for Europe. Evidence for the effectiveness and cost-effectiveness of interventions to reduce alcohol-related harm. Copenhagen, Denmark: WHO Regional Office for Europe; 2009. Lachenmeier DW, Leitz J, Schoeberl K, Kuballa T, Straub I, Rehm J. Quality of illegally and informally produced alcohol in Europe: Results from the AMPHORA project. Adicciones 2011;23(2):133-140. Lachenmeier DW, Rehm J, Gmel G. Surrogate alcohol: what do we know and where do we go? Alcohol Clin Exp Res 2007;31(10):1613-1624. Ostapenko YN, Brusin KM, Zobnin YV, Shchupak AY, Vishnevetskiy MK, Sentsov VG, et al. Acute cholestatic liver injury caused by polyhexamethyleneguanidine hydrochloride admixed to ethyl alcohol. Clin Toxicol 2011;40(6):471-477. Tsisanova ES, Salomatin EM. Forensic chemical investigation of alcohol-containing liquids doped with polyhexamethylene guanidine hydrochloride and diethylphthalate. Sud Med Ekspert 2010;53(4):33-37. Leitz J, Kuballa T, Rehm J, Lachenmeier DW. Chemical analysis and risk assessment of diethyl phthalate in alcoholic beverages with special regard to unrecorded alcohol. PLoS One 2009;4(12):e8127. Monakhova YB, Kuballa T, Leitz J, Lachenmeier DW. Determination of diethyl phthalate and polyhexamethylene guanidine in surrogate alcohol from Russia. Int J Anal Chem 2011;2011:Article ID 704795. Lachenmeier DW, Monakhova YB, Samokhvalov AV, Rehm J. Causality between polyhexamethyleneguanidine occurence in unrecorded alcohol and cholestatic hepatitis outbreak in Russia. Clin Toxicol 2011;in press. Lachenmeier DW, Kanteres F, Rehm J. Epidemiology-based risk assessment using the benchmark dose/margin of exposure approach: the example of ethanol and liver cirrhosis. Int J Epidemiol 2011;40(1):210-218. Go to the eASL Booth to know more! Join iLiver on Facebook Follow iLiver on Twitter www.iliver.eu/fb www.iliver.eu/twitter www.iliver.eu
© Copyright 2024