barcelona . spain - European Association for the Study of the Liver

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 3 

APRIL 18 - 19/2012 THE INTERNATIONAL LIVER CONGRESS TM 2012 

TABLE OF CONTENTS 

WELCOME MESSAGE 

3 

4 

5 

8 

11 

17 

25 

32 

38 

43 

54 

59 

76 

81 

87 

93 

98 

103 

112 

116 

121 

131 

136 

140 

147 

152 

158 

165 

WELCOME MESSAGE 

EASL GOVERNING BOARD 

PROGRAMME 

POSTGRADUATE COURSE FACULTY 

CONTRIBUTORS: 

H. CORTEZ-PINTO, PORTUGAL 

N. SHERON, UK 

S. ZAKHARI, USA 

F. STICKEL, SWITZERLAND 

S. LOTERSZTAJN, FRANCE 

F. MARRA, ITALY 

T. ROSKAMS, BELGIUM 

S. MUELLER, GERMANY 

A. GUAL, SPAIN 

G. ADDOLORATO, ITALY 

J. FERNÁNDEZ-SOLÀ, SPAIN 

E.H. FORREST, UK 

F. NEVENS, BELGIUM 

A. HADENGUE, SWITZERLAND 

J-C. DUCLOS-VALLÉE, FRANCE 

J. NEUBERGER, UK 

H. SEITZ, GERMANY 

T. DECAENS, FRANCE 

G.P. PAGEAUX, FRANCE 

P. BURRA, ITALY 

B. GAO, USA 

L. SPAHR, SWITZERLAND 

P. ANDERSON, UK 

D.W. LACHENMEIER, GERMANY 

Dear Colleagues, 

It is with great pleasure that we welcome you to the Postgraduate Course of the International Liver 

Congress 2012, the 47 th annual meeting of the European Association for Study of the Liver. 

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 

EASL SECRETARY GENERAL 

Prof. Markus Peck-Radosavljevic 

EASL VICE-SECRETARY




EASL GOVERNING BOARD 

PROGRAMME 

SECRETARY GENERAL 

Mark Thursz, London, UK 

WEDNESDAY, APRIL 18, 2012 

HALL A 

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 

11:30-17:30 Postgraduate Course 

ALCOHOLIC LIVER DISEASE 

Course Directors: R. Bataller, USA 



11:30 Introduction 


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 7 

POSTGRADUATE COURSE SYLLABUS 



WEDNESDAY, APRIL 18, 2012 continued 

THURSDAY, APRIL 19, 2012 

HALL A 

THE PATIENT WITH CHRONIC ALD 

14:00 Q&A INTERACTIVE SESSION: CLINICAL CASE (QUESTIONS) 

Fellow: F. Artru, France 

14:05 HISTOLOGICAL ASSESSMENT OF ALD 

T. Roskams, Belgium 

08:30-12:00 Postgraduate Course 


Course Directors: R. Bataller, USA 



LONG-TERM MANAGEMENT OF ALD 

14:20 NONINVASIVE TOOLS IN THE DIAGNOSIS OF ALD 

S. Mueller, Germany 

14:35 ABUSE OR DEPENDENCE ASSESSING THE ALCOHOLIC PATIENT 

IN THE CLINIC 

A. Gual, Spain 

14:50 MANAGEMENT OF ALCOHOL DEPENDENCE IN PATIENTS WITH ALD 

G. Addolorato, Italy 

15:05 EXTRAHEPATIC INVOLVEMENT IN PATIENTS WITH ALD 

J. Fernández-Solà, Spain 

15:20 Q&A INTERACTIVE SESSION: CLINICAL CASE (ANSWERS) 

A. Louvet, France 

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 ALCOHOLIC HEPATITIS OR DECOMPENSATED CIRRHOSIS: DIAGNOSTIC 

AND PROGNOSTIC ISSUES 

F. Nevens, Belgium 

16:35 MANAGEMENT OF ALCOHOLIC HEPATITIS 


CONTROVERSY: CAN WE OFFER LIVER TRANSPLANTATION TO PATIENTS WITH 

ALCOHOLIC HEPATITIS 

16:50 YES 

J-C. Duclos-Vallée, France 

17:05 NO 

J. Neuberger, UK 

17:20 Q&A INTERACTIVE SESSION: CASE PRESENTATION (ANSWERS) 

J. Caballería, Spain 

08:30 Q&A INTERACTIVE SESSION: CASE PRESENTATION (QUESTIONS) 

Fellow: N. Goossens, Switzerland 

08:35 ALCOHOL CONSUMPTION AS A CO-FACTOR FOR OTHER 

LIVER DISEASES 

H. Seitz, Germany 

08:50 HEPATOCELLULAR CARCINOMA: IS IT DIFFERENT IN PATIENTS 

WITH ALD 

T. Decaens, France 

09:05 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 

FUTURE PROSPECTS IN ALD 

10:30 NOVEL TARGETS FOR THERAPY IDENTIFIED IN TRANSLATIONAL STUDIES 

B. Gao, USA 

10:45 STEM CELLS IN ALD: THE ROAD FROM ANIMAL MODELS TO HUMAN 

STUDIES 

L. Spahr, 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 


P. Mathurin, France 

11:55 CONCLUDING REMARKS 

R. Bataller, USA


8 9 

POSTGRADUATE COURSE SYLLABUS 



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: 

R. Bataller, USA 



EASL EDUCATIONAL COUNCILLORS: 

J. Dufour, Switzerland 


Antoine HADENGUE 

Division of Gastroenterology and Hepatology, Cantonal Hospital, Geneva, Switzerland 

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 

Jose T. ALTAMIRANO 

Liver Unit, Liver Fibrosis Laboratory, Hospital Clinic, Barcelona, Spain 

Peter ANDERSON 

Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK 

Florent ARTRU 


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 

Juan CABALLERÍA 

Liver Unit, Hospital Clinic, Barcelona, Spain 

Helena CORTEZ-PINTO 

Department of Gastroenterology, Hospital of Santa Maria, Unit of Nutrition and Metabolism, FML, Instituto de 

Medicina Molecular (IMM), Lisbon, Portugal 

Andrea DE GOTTARDI 

University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland 

Thomas DECAENS 

Department of Hepatology, Henri Mondor Hospital, University of Paris, Créteil, France 

Jean-Charles DUCLOS-VALLÉE 

Centre Hépato-Biliaire, Hôpital Paul-Brousse, Villejuif, France 

Jean Francois DUFOUR 

University Clinic of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland 

Joaquim FERNÁNDEZ-SOLÀ 

Alcohol Unit, Department of Medicine, Hospital Clínic, University of Barcelona, Spain 

Ewan FORREST 

Department of Gastroenterology, Glasgow Royal Infirmary, Castle Street, Glasgow, UK 

Sophie LOTERSZTAJN 

Inserm U955, Hospital Henri Mondor, Créteil, France 

Fabio MARRA 

Department of Internal Medicine, University of Florence, Florence, Italy 

Philippe MATHURIN 


Sebastian MUELLER 

Department of Medicine, Salem Medical Centre and Centre for Alcohol Research, University of Heidelberg, 

Heidelberg, Germany 

Frederik NEVENS 

Department Liver and Biliopancreatic diseases, University Hospital Gasthuisberg, K.U. Leuven, Belgium 

James NEUBERGER 

Liver Unit, Queen Elizabeth Hospital, Birmingham, UK 

Georges-Philippe PAGEAUX 

Department of Hepato-Gastroenterology, CHU Saint Eloi, Montpellier, France 

Tania ROSKAMS 

Department of Morphology and Molecular Pathology, University of Leuven, Leuven, Belgium 

Helmut SEITZ 

Centre of Alcohol Research, University of Heidelberg and Department of Medicine, Salem Medical Centre, 


Nick SHERON 

Department of Clinical Hepatology, University of Southampton, Southampton, UK 

Laurent SPAHR 

Division of Gastroenterology and Hepatology, Geneva University Hospital, Geneva, Switzerland 

Felix STICKEL 

Department of Visceral Surgery and Medicine, Inselspital, University of Bern, Switzerland 

Sam ZAKHARI 

Division of Metabolism and Health Effects, National Institute on Alcohol Abuse and Alcoholism, National 

Institutes of Health, Bethesda, USA 

Fabien ZOULIM 

Liver Department, Hôtel Dieu Hospital & Hepatitis Research Laboratory, Lyon, France



11 

INCREASING BURDEN OF ALCOHOLIC LIVER DISEASE IN EUROPE 

COME AND 

VISIT THE 

EASL BOOTH 

RENEW 

YOUR MEMBERSHIP 

JOIN THE 

EASL COMMUNITY 

TODAY 

Helena Cortez-Pinto 

Lisbon, Portugal 

E-mail: hlcortezpinto@netcabo.pt 

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. 

EASL Office 

easloffice@easloffice.eu 

www.easl.eu 

membership@easloffice.eu




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 

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.




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. 

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.




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. 

ALCOHOLIC LIVER DISEASE IN EUROPE 

Nick Sheron 

Southampton, UK 

E-mail: nick.sheron@soton.ac.uk 

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 

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




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 1 st centuries BC 

and AD, and by Saints Boniface and Bede in the 9 th 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 mid- 

1990’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 

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-




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. 

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/ 

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




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. 

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). 

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




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. 

PATTERNS OF ALCOHOL INTAKE AND ALD: EFFECTS OF BINGE 

DRINKING ON THE LIVER 

Sam Zakhari 

Bethesda, Maryland, USA 

E-mail: zakhari@willco.niaaa.nih.gov 

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.”




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 (H 2 

O 2 

)- 

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 CO 2 

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. 

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 (H 2 

O 2 

). Mitochondrial glutathione peroxidase 

(GPx) then converts H 2 

O 2 

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 H 2 

O 2 

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 CO 2 

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 CO 2 

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.




Figure 1 

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; H 2 

O 2 

= 

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.




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. 

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NATURAL HISTORY OF ALD: ROLE OF ENVIRONMENTAL 

AND GENETIC FACTORS 

Felix Stickel 

Bern, Switzerland 

E-mail: Felix.stickel@ikp.unibe.ch 

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.




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). 

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.




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 

Study Design Patients Results 

Tian et al. * 

Seth et al. * 

Trépo et al. * 

Stickel et al. * 

Genetic case control 

482 cases (alcoholic 

cirrhosis) (Mestizo 

subjects with strong 

ethnic heterogeneity) 


(British 

Caucasians) 


(Belgium Caucasians) 


(German Caucasians) 

482 cases (alcoholic cirrhosis) 

434 non-cirrhotic ALD 

305 alcoholics w/o liver 

enzyme elevations 

266 cases (alcoholic cirrhosis) 

182 controls (heavy drinkers 

w/o clinical ALD) 

330 cases (97% biopsyproven 

ALD; 263 cirrhotics) 

328 controls (healthy 

individuals without ALD) 

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) 

rs738409 GG associated with cirrhosis 

when compared to controls (OR 2.25, 1.74- 

2.9; 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 ) 

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, 1.34- 

2.84, p=0.00002) 

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 

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% 

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. 

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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. 

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risk of 15 diseases. Prev Med 2004;38:613-619. 

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Gleeson D, Evans S, Bradley M, et al. HFE genotypes in decompensated alcoholic liver disease: 

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Marcos M, Gómez-Munuera M, Pastor I, et al. Tumor necrosis factor polymorphisms 

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* For full reference, please see ref. 11.




NOVEL MECHANISMS OF ALCOHOLIC STEATOHEPATITIS 

Sophie Lotersztajn 

Créteil, France 

E-mail: sophie.lotersztajn@inserm.fr 

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 

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




(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. 

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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. 

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.




Figure 1 

MECHANISMS OF ALCOHOL-INDUCED LIVER FIBROSIS 

Fabio Marra 

Florence, Italy 

E-mail: f.marra@dmi.unifi.it 

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




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. 

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. 

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. 

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 

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. 

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. 

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. 

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. 

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




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. 

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. 

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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. 

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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: 

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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;16:1321- 

Tam 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. 

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.




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: p-mathurin@chru-lille.fr 

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/m 2 

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/mm 3 , hemoglobin 14.5 g/dL, MCV (mean corpuscular volume) 101 fl, platelet count 

135,000/mm 3 , 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




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 

for the development of cirrhosis (2). Alcoholic and non-alcoholic fatty liver disease share similar pathways 

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




NOTES 

disulfiram. The most promising drug for the maintenance of abstinence in alcoholic cirrhotic patients is 

baclofen. Baclofen is an agonist of the GABA B 

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 

more than 50 g per week in men in a recent meta-analysis (17). 

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. 

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. 

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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. 


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. 


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Altamirano J, Bataller R. Cigarette smoking and chronic liver diseases. Gut 2010;59:1159-1162. 

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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;83:1351- 

1354; 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 

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Hepatol 2008;49:1062-1068. 

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randomized controlled trial. Jama 2005;293:1617-1625.




HISTOPATHOLOGICAL ASSESMENT OF ALCOHOLIC LIVER DISEASE 

Tania Roskams 

Leuven, Belgium 

E-mail: tania.roskams@uz.kuleuven.ac.be 

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. 

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




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. 

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.




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. 


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 7 th meeting of the International Ascites Club. 

Gut2005; 54;718-725 

NONINVASIVE TOOLS IN THE DIAGNOSIS OF ALD 

Sebastian Mueller 


E-mail: sebastian.mueller@urz.uni-heidelberg.de 

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 (




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 

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




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. 

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, 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




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 

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 

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.




Figure 3 

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 6 

Figure 5




Figure 7 

Figure 9 

Figure 8 

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




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. 

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




Figure 14 

Figure 16 

Figure 15 

Figure 17




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Castera L. Non-invasive assessment of liver fibrosis in chronic hepatitis C. Hepatol Int 2011; 

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Naveau S GG, Asnacios A, Agostini H, Abella A, Barri-Ova N, Dauvois B, Prevot S, Ngo Y, 

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Hepatology 2009;49:97-105. 

Nguyen-Khac E, Chatelain D, Tramier B, Decrombecque C, Robert B, Joly JP, et al. Assessment 

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ABUSE OR DEPENDENCE ASSESSING THE ALCOHOLIC 

PATIENT IN THE CLINIC 

Antoni Gual 

Barcelona, Spain 

E-mail: TGUAL@clinic.ub.es 

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 

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 40g 60g 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




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 

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.




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. 

MANAGEMENT OF ALCOHOL DEPENDENCE IN PATIENTS WITH ALD 

Giovanni Addolorato 

Rome, Italy 

E-mail: g.addolorato@rm.unicatt.it 

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




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, 

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 12- 

week 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.




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. 

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. 

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.




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 alcoholdependent 

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 

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for alcohol and drug addiction: focus on GABA, Ion channels and transcranial magnetic 

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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. 

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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. 

EXTRAHEPATIC INVOLVEMENT IN PATIENTS WITH CHRONIC 

ALCOHOL LIVER DISEASE 

Joaquim Fernández-Solà 


E-mail: jfernand@clinic.ub.es 

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 proinflammatory 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




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. 

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




NOTES 

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: 363- 

377. 

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, Muñoz- 

Gómez J.Reduced spinal and femoral bone mass and deranged bone mineral metabolism in 

chronic alcoholics.Alcohol Alcohol. 1992; 27(6):619-625. 

CLINICAL CASE : THE ACUTELY ILL PATIENT 

J. Altamirano, 

J. Caballería 


E-mail: jtaltami@clinic.ub.es 

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.




THE ACUTELY ILL PATIENT: ALCOHOL WITHDRAWAL 

Table 1 At admission Day 2 Day 7 

WBC (109/l) 12.2 

11.3 

Hemoglobin (gr/dl) 11.7 10.8 11 

Platelets (109/l) 

100 

13.1 

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 3.1 

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 65 

HBsAg 

Anti-HCV Abs 

Negative 

Negative 

Blood cultures Negative + (P. Aeruginosa) 

Urine cultures Negative Negative 

Ewan Forrest 

Glasgow, UK 

E-mail: Ewan.Forrest@ggc.scot.nhs.uk 

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.




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. 

(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 


3. How often during the last year have you failed to what was normally expected of you because of drinking 

Never 


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 

0 Yes, on one occasion 2 Yes, on more than one occasion 4 

FAST≥3 indicates hazardous drinking behavior. 

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




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: 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 

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ALCOHOLIC HEPATITIS OR DECOMPENSATED CIRRHOSIS: 

DIAGNOSTIC AND PROGNOSTIC ISSUE 

Frederik Nevens 

Leuven, Belgium 

E-mail: frederik.nevens@uzleuven.be 

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 

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




(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). 

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). 

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ALCOHOLIC STEATOHEPATITIS (ASH) 

Antoine Hadengue 

Geneva, Switzerland 

E-mail: antoine.hadengue@gmail.com 

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




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]. 

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. 

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 

rapidly during the course of ASH, while the healing process can be accompanied by a marked decrease in 

portal pressure over a few weeks. 

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]. 

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. 

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 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 0.56, had 

50% survival under steroids, which was slightly inferior to the 56% survival in patients not receiving steroids




(NS). Thus, the Lille score is particularly useful to establish a stopping rule in non-responders at day 7 of 

steroid therapy (see below). 

TREATMENT IN ALL FORMS OF ASH 

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 

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. 

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. 

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].




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. 

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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 0.56). From Mathurin P et al. Gut 2011 [25] with permission.




CAN WE OFFER LIVER TRANSPLANTATION TO PATIENTS WITH 

ALCOHOLIC HEPATITIS ANSWER: YES 

Jean-Charles Duclos-Vallée 

Villejuif, France 

E-mail: jean-charles.duclos-vallee@pbr.aphp.fr 

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 post- 

LT 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 

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




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. 

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. 

REFERENCES 

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.




CAN WE OFFER LIVER TRANSPLANTATION TO PATIENTS WITH 

ALCOHOLIC HEPATITIS 

ANSWER: NO 

James Neuberger 

Bristol, UK 

E-mail: j.m.neuberger@bham.ac.uk 

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 

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




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. 

CLINICAL CASE: LONG-TERM MANAGEMENT OF ALD 

A. De Gottardi 


N. Goossens 


E-mail: Nicolas.Goossens@hcuge.ch 

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. 

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, 


**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.




NOTES 




N. Goossens 
















ALCOHOL CONSUMPTION AS A CO-FACTOR FOR OTHER LIVER 

DISEASES 

Helmut K. Seitz 


E-mail: helmut_karl.seitz@urz.uni-heidelberg.de 

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).




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. 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. 

2. 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. 

3. It is still unclear how long a patient has to be alcohol abstinent until a negative effect of 

alcohol disappears. 

4. 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. 

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 H 2 

O 2 

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.




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Seitz HK, Mueller S. Alcohol metabolism and its consequences. In in press 

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Figure 1 

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Figure 2 

Figure 5 

Figure 3 

Figure 6 

Figure 4 

Figure 7




Figure 8 

Figure 11 

Figure 9 

Figure 12 

Figure 10 

Figure 13




Table 1 

HEPATOCELLULAR CARCINOMA: IS IT DIFFERENT IN PATIENTS 

WITH ALCOHOLIC LIVER DISEASE 

Thomas Decaens 

Creteil, France 

Email: thomas.decaens@hmn.aphp.fr 

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 death 1 . 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) report 2 , 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 sample 3 . 

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 populations 4 . Compared to the increase 

in alcohol consumption, it is of note that HBV infection 5 and HCV infection 6 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




(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. 

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 Asia 8 . 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 USA 8 . 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. 

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 

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. 

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. 

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 differs 10 . 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 differences 11 . 

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 hepatitis 12 . 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




a transplant, even after excluding patients who are still actively drinking 13 . 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. 

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 2005 2 

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 study 7 . 

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.




LONG-TERM MANAGEMENT OF ALCOHOLIC LIVER DISEASE 

EVALUATION AND SELECTION OF CANDIDATES FOR LIVER 

TRANSPLANTATION 

Georges-Philippe Pageaux 

Montpellier, France 

E-mail: gp-pageaux@chu-montpellier.fr 

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 

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.




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. 

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. 

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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 

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.




PATIENTS WITH ALCOHOLIC LIVER DISEASE AND LIVER 

TRANSPLANTATION: SPECIFIC ISSUES 

Patrizia Burra 

Padova, Italy 

E-mail: burra@unipd.it 

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-Turcotte- 

Pugh 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




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]. 

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. 

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]. 

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]. 

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]. 

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%). 

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]. 

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]. 

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]. 

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]. 

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]. 

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]. 

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]. 

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. 

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.




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. 

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Neuberger J. Transplantation for alcoholic liver disease: a perspective from Europe. 

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Poynard T, Naveau S, Doffoel M, Boudjema K, Vanlemmens C, Mantion G, et al. 

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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 

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Anand AC, Ferraz-Neto BH, Nightingale P, Mirza DF, White AC, McMaster P, et al. 

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1995;23:474-479. 

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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. 

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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: 

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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. 

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for alcoholic cirrhosis. Transplantation 1999;67:418-421. 

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cell carcinoma after liver transplantation for alcohol-induced cirrhosis. Transpl Int 2003;16:639-641. 

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of liver disease and medical complications on quality of life and psychological distress before 

and after liver transplantation. J Hepatol 2000;33:609-615. 

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Comparing quality of life following liver transplantation for Laennec’s versus 

non-Laennec’s patients. Clin Transplant 2000;14:115-120. 

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et al. General compliance after liver transplantation for alcoholic cirrhosis. Transpl Int 2000;13: 

129-135. 

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Societal reintegration after liver transplantation: findings in alcohol-related and 

non-alcohol-related transplant recipients. Ann Surg 2004;239:93-98. 

NOVEL TARGETS FOR ALCOHOLIC LIVER DISEASE (ALD) THERAPY 

IDENTIFIED IN TRANSLATIONAL STUDIES 

Bin Gao 

Bethesda, Maryland, USA 

E-mail: bgao@mail.nih.gov 

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.




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. 

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).




NOTES 




N. Goossens 





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. 












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STEM CELLS IN ALCOHOLIC LIVER DISEASE: THE ROAD FROM 

ANIMAL MODELS TO HUMAN STUDIES 

Laurent Spahr 


E-mail: Laurent.Spahr@hcuge.ch 

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. 

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.




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] 

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. 

Harb (2009) 

Li (2010) 

Monocrotaline + 

radiation in rats 

Radiation injury in 

mice 

No G-CSF 

5 x 10 6 unsorted BM 

Cells 

G-CSF + 

10 5 CD34+ cells 

Tail vein 

Tail vein 

Improved liver repair 

via SEC of BM origin 


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) 

Terai (2003) 

Kuo (2008) 

Piscaglia (2007) 

Model 

CCl 4 

in mice 

CCl 4 

in NOD-SCID 

mice 

Radiation injury in 

rats 

Transplantation 

protocol 

No G-CSF 

10 5 unsorted BM 

Cells 

No G-CSF 

1.4 x 10 6 MSC/kg 

G-CSF + 

5 x 10 7 unsorted BM 

Cells 

Route 

Tail vein 

Intravenous 

Tail vein 

Outcome 

Evidence of 

transdifferentiation 

25% repopulation of 

damaged liver 

Stimulation of 

endogenous 

hepatocyte 

proliferation 

Endogenous oval cell 

stimulation 


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. 

Table 2: Selected list of uncontrolled clinical studies of autologous BM- derived cells transplantation 

in chronic liver disease 

Author (yr) Pts (n) Clinical setting Protocol Route Outcome 

Terai (2006) 9 

Gordon (2006) 5 

Mohamadnejad 

(2007) 

4 

Pai (2008) 9 

Viral compensated 

cirrhosis 

Cirrhosis 

(4 = alcoholic) 

Decompensated 

cirrhosis (mixed 

etiology) 

Abstinent alcoholic 

cirrhosis 

No G-CSF 

BMA+ 

78 x 10 9 

MNC 

G-CSF+ 

No BMA 

10 6 -10 8 

CD34+ cells 

No G-CSF 

BMA+ 

3 x 10 6 

CD34+ cells 

G-CSF + 

No BMA 

2 x 10 8 

MNC 

Peripheral 

vein 

PV = 3 

HA = 2 

HA 

HA 

Improved Child-Pugh 

score at 6 months 

Modest improvement 

in biological 

parameters 

Major side effect 

Improvement in 

Child-Pugh score at 3 

months




Table 3 : Controlled clinical studies of autologous BM- derived cells transplantation in chronic liver 

disease 

Abbreviations: BM: bone marrow; ALD: alcoholic liver disease; ASH: alcoholic steatohepatitis; G-CSF: 

granulocyte colony-stimulating factor; RCT: randomized controlled trial 

Author (yr) Patients (n) Clinical setting Protocol Route Outcome 

Lyra 

(2010) 

Peng (2011) 53 

Spahr (2011) 28 

15 Cirrhosis on LT list 

Decompensated 

chronic Hep B 

Decompensated 

alcoholic liver 

disease 

No G-CSF 

BMA+ 

No G-CSF 

BMA+ 

3.4 x 10 8 MNC 

G-CSF + 

BMA+ 

0.47 x 10 8 MNC/k 

HA 

HA 

HA 

Transient 

improvement in 

bilirubin 

Transient 

improvement in MELD 

score 

No benefit 

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) 

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.




CURRENT POLICIES TO REDUCE THE HARM DONE BY ALCOHOL 

Peter Anderson 

Newcastle upon Tyne, UK 

E-mail: peteranderson.mail@gmail.com 

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




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




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. 

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 

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




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Copenhagen, World Health Organization Regional Office for Europe, 2009. 

ILLEGALLY PRODUCED SPIRITS IN EASTERN EUROPE: TO WHAT 

EXTENT AND AT WHAT RISK 

Dirk W. Lachenmeier 

Karlruhe, Germany 

E-Mail: Lachenmeier@web.de 

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).




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) 

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




Table 1. Compounds potentially associated with toxicity in unrecorded alcohol 

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) 

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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 

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