Alcohol And the Gastrointestinal Tract: Special Issue: Digestive Diseases 2005

Alcohol and the Gastrointestinal Tract Editors Manfred V. Singer, Mannheim David Brenner, New York, N.Y. 36 ﬁgures, 15...

Author: M. V. Singer | D. Brenner

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Alcohol and the Gastrointestinal Tract Editors

Manfred V. Singer, Mannheim David Brenner, New York, N.Y.

36 ﬁgures, 15 tables, 2005

Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Singapore • Tokyo • Sydney

S. Karger Medical and Scientiﬁc Publishers Basel • Freiburg • Paris • London New York • Bangalore • Bangkok Singapore • Tokyo • Sydney

Disclaimer The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant ﬂow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.

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Vol. 23, No. 3–4, 2005

Contents

161 Editorial Singer, M.V. (Mannheim); Brenner, D.A. (New York, N.Y.)

232 Molecular Mechanisms of Alcoholic Pancreatitis Apte, M.V.; Pirola, R.C.; Wilson, J.S. (Sydney)

162 Measuring the Health Consequences of Alcohol

241 Treatment of Alcoholic Pancreatitis Pfützer, R.H.; Schneider, A. (Mannheim)

Consumption: Current Needs and Methodological Challenges

247 Genetic Polymorphisms in Alcoholic Pancreatitis Whitcomb, D.C. (Pittsburgh, Pa.)

Bloss, G. (Bethesda, Md.) 170 Moderate Alcohol Consumption and the

255 Clinical Syndromes of Alcoholic Liver Disease Adachi, M.; Brenner, D.A. (New York, N.Y.)

Gastrointestinal Tract Taylor, B. (Toronto); Rehm, J. (Toronto/Zürich); Gmel, G. (Toronto/Lausanne)

264 Molecular Mechanisms of Alcohol-Induced Hepatic

Fibrosis

177 Moderate Alcohol Consumption and Diseases of

Siegmund, S.V. (New York, N.Y./Heidelberg); Dooley, S. (Heidelberg); Brenner, D.A. (New York, N.Y.)

the Gastrointestinal System: A Review of Pathophysiological Processes Taylor, B.; Rehm, J. (Zürich) 181 Animal Models and Their Results in Gastrointestinal

Alcohol Research Siegmund, S.V. (Heidelberg/New York, N.Y.); Haas, S.; Singer, M.V. (Heidelberg) 195 Alcohol-Related Diseases of the Mouth and Throat Riedel, F.; Goessler, U.R.; Hörmann, K. (Mannheim) 204 Alcohol-Related Diseases of the Esophagus and

Stomach

285 Alcohol and Hepatitis C Jamal, M.M.; Saadi, Z.; Morgan, T.R. (Long Beach, Calif.) 297 Alcohol Consumption and Cancer of the

Gastrointestinal Tract Seitz, H.K.; Maurer, B.; Stickel, F. (Heidelberg) 304 Therapy and Supportive Care of Alcoholics:

Guidelines for Practitioners

Franke, A. (Mannheim); Teyssen, S. (Bremen); Singer, M.V. (Mannheim) 214 Effect of Alcohol Consumption on the Gut Rajendram, R. (London/Oxford); Preedy, V.R. (London) 222 Alcoholic Pancreatitis Schneider, A.; Singer, M.V. (Mannheim)

© 2005 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

275 Treatment of Alcoholic Liver Disease Bergheim, I.; McClain, C.J.; Arteel, G.E. (Louisville, Ky.)

Access to full text and tables of contents, including tentative ones for forthcoming issues: www.karger.com/ddi_issues

Kienast, T.; Heinz, A. (Berlin)

310 Author Index Vol. 23, 2005 311 Subject Index Vol. 23, 2005 after 312 Contents Vol. 23, 2005

Dig Dis 2005;23:161 DOI: 10.1159/000090161

Editorial

Alcohol-related disorders account for an enormous part of the global mortality and for an even greater part of the life years lost by disabilities due to alcohol consumption. In Europe and the USA, more than 20% of men and approximately 9% of women hospitalized in varying medical departments in general hospitals feature alcoholrelated disorders. In Germany, alcohol-induced diseases caused direct or indirect costs of about 20.6 billion EUR in the year 2000. Strikingly, most of the patients with alcohol-induced organic disorders are being treated in gastroenterology. Thus, our aim in this issue of Digestive Diseases was to provide state-of-the-art reviews by a team of internationally well-renowned experts on alcohol-related epidemiology as well as diseases of the gastrointestinal tract, liver and pancreas. In addition, we also wanted to provide strategies on how to guide alcoholic patients psychologically, because not only do alcohol use and abuse contribute to a variety of medical disorders, but they can strongly affect the social, socioeconomic and personal situation of these patients such as family interactions or worker productivity. Alcohol abuse can kill, both directly and indirectly; it results in an increase in the number of injuries, automobile collisions and violence-related deaths. Therefore, any physician who wants to successfully treat patients who suffer alcohol-related diseases should not only treat the medical conditions. This issue starts with an overview of the epidemiological data on the impact of alcohol consumption on to-

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tal morbidity and mortality. Moreover, recent evidence from epidemiology studies suggests that moderate alcohol consumption might have some health beneﬁt, mainly by lowering the risk of coronary heart disease in a certain subset of the population. Therefore, we present critical evaluations of the impact of moderate alcohol consumption on the risk and the pathophysiological mechanisms of gastrointestinal diseases. An appraisal of the available animal models used for the study of alcohol-related diseases explains the latest ﬁndings in basic alcohol research. The effects of alcohol on the various parts of the gastrointestinal system are discussed in separate chapters with special emphasis on the pancreas and liver. A review of the well-known association between alcohol consumption and increased risk of cancer is followed by a discussion on how best to care for alcoholics in view of the advances presented in alcohol research. We would like to thank the international experts who contributed well-organized and well-written summaries of the current knowledge in this ﬁeld, and have successfully presented up-to-date and solid scientiﬁc data on the subject. We would also like to thank Dr. Peter Feick for his reliable assistance in the preparation of this issue. It has also been a great pleasure to correspond with the authors. We do hope that readers ﬁnd this issue of Digestive Diseases fulﬁls their expectations. Manfred V. Singer, Mannheim David A. Brenner, New York

Dig Dis 2005;23:162–169 DOI: 10.1159/000090162

Measuring the Health Consequences of Alcohol Consumption: Current Needs and Methodological Challenges Gregory Bloss National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services, Bethesda, Md., USA

Key Words Mortality, alcohol-attributable Health consequences, alcohol Alcohol abuse

Abstract Background/Aims: Extensive research has shown that alcohol consumption leads to poor health and premature death through its causal or contributing roles in numerous chronic health conditions and acute health outcomes, including various cancers, liver disease, and injuries. Paradoxically, advances in understanding of the causal associations between alcohol consumption and various conditions have complicated our ability to discern trends in the health consequences of alcohol consumption over time. Methods: Four distinct needs for information on alcohol’s role in causing adverse health outcomes are identified. Estimates of alcohol-attributable mortality from two US studies are compared and differences identified. Results: Differences in the conditions included and alcohol-attributable fractions employed accounted for large differences in the estimated alcohol-attributable mortality for several health outcomes. Conclusion: Despite the broad consensus on many health consequences of alcohol consumption, further research is needed to clarify the conditions that are caused by alcohol consumption, magnitudes of causal relationships, and effects of different patterns of con-

© 2005 S. Karger AG, Basel Fax +41 61 306 12 34 E-Mail [email protected] www.karger.com

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sumption and individual characteristics. Comparisons over time are needed to identify areas where improvements in public health may be occurring or are most needed, to support evaluation of specific interventions, and to encourage the public awareness of alcohol problems that is necessary to change attitudes and behaviors involving alcohol consumption. Copyright © 2005 S. Karger AG, Basel

Introduction

There is clear scientiﬁc consensus that alcohol consumption leads to a variety of harms to health, and substantial agreement regarding many speciﬁc health consequences that result from excessive alcohol consumption. Several recent reviews and meta-analyses provide surveys of the epidemiological evidence regarding alcohol effects for various health outcomes [1–5]. Nevertheless, further research effort devoted to discovering and documenting the nature and extent of those harms is clearly needed. Four distinct needs for this information – clinical, individual, scientiﬁc, and social – justify further work to assess the health consequences of alcohol consumption. First, advances in knowledge of the effects of alcohol on speciﬁc health outcomes support good clinical practice, including appropriate identiﬁcation of causal factors underlying patients’ health conditions and guidance to clini-

Gregory Bloss NIAAA Division of Epidemiology and Prevention Research 5635 Fishers Lane, Room 2075 Bethesda, MD 20892-9304 (USA) Tel. +1 301 443 3865, Fax +1 301 443 8614, E-Mail [email protected]

cians regarding other conditions that may threaten the health of individual patients. The variety of health conditions associated with alcohol consumption, and the possibility that individuals may deny the existence of an alcohol problem, make it important for physicians to be well-informed about these effects. Awareness of the potential health consequences of alcohol consumption also supports appropriate screening and intervention by primary care clinicians [6, 7]. The limits to current knowledge regarding the relationships between consumption at various levels and the risks for speciﬁc outcomes, as well as the subtler issues involving co-variation in risks across different population groups and different levels and patterns of alcohol consumption, leave important areas of uncertainty that underscore the need for further research. Second, clearer information than that currently available will assist in evaluating the risks and beneﬁts associated with alcohol-related behaviors that may be contemplated. Rational individual decisions about alcohol consumption may appear difﬁcult in the context of an extensive list of associated health conditions and an uncertain schedule of risks and beneﬁts that vary in different ways across conditions by age and sex, as well as by levels, patterns, and contexts of consumption. In addition, the evidence of signiﬁcant beneﬁcial effects for at least some population groups may reduce the attraction of abstention even among those who are highly averse to health risks. Individuals need information to help address not just the global questions of ‘how much, how often?’ but the more immediate issue of ‘Should I have a(nother) drink now?’ Although full-blown risk-beneﬁt calculations cannot be part of every interaction with a bartender or social host, clearer understanding of the scope, severity, and speciﬁc risks of potential health consequences can contribute to better planning and ultimately better outcomes. Third, there are continuing scientiﬁc opportunities to be explored in terms of additional conditions that may be caused (or prevented) by alcohol consumption and revisions to previous understanding of the relationships between consumption and conditions that have already been identiﬁed as alcohol-related. The major areas of scientiﬁc focus continue to be on identifying, characterizing, and quantifying associations between alcohol consumption and various disease and other health outcomes and in describing the causal mechanisms that underlie such associations. To address the clinical, individual, and social needs identiﬁed here, the most important scientiﬁc opportunities involve advancing understanding of how

Measuring Health Consequences of Alcohol Consumption

speciﬁc patterns of consumption interact with individual characteristics to affect overall health risks and beneﬁts. This represents a large and important research agenda whose scope encompasses the many known conditions for which risk may be affected multiplied by the many permutations of individual characteristics and consumption patterns, as well as additional conditions that may yet be linked to alcohol consumption. Given the great breadth of this research agenda, a key priority is to strengthen measurement approaches that apply across the full range of conditions. Particular needs include further reﬁnement in measurement of alcohol consumption levels and patterns as well as development, testing, and validation of metrics and assessment tools that support comparisons of health outcomes at both the individual and aggregate levels. Advances in these areas will support further progress in the broader scientiﬁc goal of developing a rich and detailed understanding of the full spectrum of alcohol effects on health. Fourth, continued research on the health consequences of alcohol consumption is needed for social purposes: to provide up-to-date information on the range and magnitude of speciﬁc risks associated with particular consumption behaviors. Credible and reliable data on the health effects of alcohol consumption can serve to focus public attention on a major public health issue, provide valid metrics for evaluating progress (or the lack thereof) in reducing adverse consequences through health-promotion programs and policies, and justify public and private interest and investment in a range of research, prevention, and treatment efforts. Addressing this need requires more than just measurement of the individual and aggregate health effects of alcohol consumption, but also tracking of how those effects change over time, i.e., reliable and comparable data on trends in alcohol-related health consequences. Recent work by the US Centers for Disease Control and Prevention to provide public web-based access to Alcohol-Related Disease Impact software that allows consistent calculation of alcohol-attributable fractions (AAFs) represents an important and constructive step in this direction [8].

Lessons from Recent Studies of AlcoholRelated Mortality in the United States

To see the potential social importance of advancing measurement of alcohol-attributable health consequences, it is instructive to consider how the collection, validation, reporting, and analysis of data on alcohol-at-

Dig Dis 2005;23:162–169

163

Fig. 1. US alcohol- and non-alcohol-related

trafﬁc fatalities per 100,000 population, 1982–2004. Source: Fatality Analysis Reporting System, National Highway Trafﬁc Safety Administration and US Census Bureau. Courtesy of R. Hingson, NIAAA.

tributable trafﬁc crash fatalities in the US over the past 25 years has contributed to successful efforts to reduce alcohol-related trafﬁc crash deaths. Since the 1970s, the Fatality Analysis Reporting System (FARS; previously known as the Fatal Accident Reporting System) of the US National Highway Trafﬁc Safety Administration has collected and reported data on trafﬁc crash fatalities in a systematic framework. Detailed information on alcohol involvement, based on physical testing of drivers involved in fatal crashes, has been part of the FARS data from the early 1980s, and this has provided a rich source of data to serve as input to many studies of efforts to reduce alcohol-related crash fatalities. The FARS data also have provided a consistent and reliable source of information for use in publicizing both the enormous burden of alcohol-related crashes and the potential value of successful interventions. The long-term success of the dual strategy of scientiﬁc analysis and publicity may be seen in the overall trends in alcohol-related trafﬁc crash fatalities: from 1982 to 2004, alcohol-related trafﬁc crash death rates in the US have declined by 50% even as trafﬁc fatalities not involving alcohol have increased by 15% over the same period (ﬁg. 1). Our ability to assess and celebrate this success, as well as a portion of the success itself, may be traced to the development and consistent reporting of outcome data on the role of alcohol in trafﬁc crash deaths.

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Dig Dis 2005;23:162–169

The situation is considerably different with respect to many other alcohol-attributable health outcomes, especially for chronic conditions associated with long-term alcohol consumption. Although there is general agreement on many speciﬁc conditions that may be wholly or partially attributed to alcohol consumption, there are some clinically and epidemiologically important conditions for which scientiﬁc agreement is very recent and not yet ﬁrmly established. Within the past 10–20 years there have been signiﬁcant revisions in our understanding of the speciﬁc conditions that may be caused by alcohol consumption and the magnitude of alcohol’s causal effects, including the identiﬁcation of conditions not previously associated with alcohol (e.g., breast cancer) and deletion of conditions once thought to be partially caused by alcohol consumption (e.g., pneumonia and inﬂuenza). In addition, there is growing consensus that moderate alcohol consumption confers a degree of protection against coronary heart disease for at least some population groups; this important effect on the leading cause of death remained controversial until quite recently. Similarly, evidence is now growing that moderate alcohol consumption may confer a protective effect for some against type-2 diabetes, a qualitative reversal from the received scientiﬁc wisdom of just a decade ago [9, 10]. A clear illustration of the effects of changing scientiﬁc assessments of the role of alcohol in mortality from vari-

Bloss

ous conditions is apparent in a comparison between two recent estimates of alcohol-attributable deaths in the US. Table 1 shows estimated alcohol-attributable mortality in the US from various causes reported for 1995 by McGinnis and Foege [11] and for 2001 by Midanik et al. [12]. The totals at the bottom of the table suggest a decrease of approximately 28% in alcohol-attributable mortality over the period. However, examination of the numbers of deaths estimated within various disease categories shows so much greater variation that it seems improbable that the health consequences of alcohol could have changed so much in such a short time. There is reasonable consistency in the components of the unintentional injuries and intentional injuries categories, but major discrepancies in deaths attributed to toxicity/overdose and to a number of chronic health conditions. An obvious source of disparity in the chronic conditions category is that each study reports substantial numbers of deaths from conditions for which the other study reports zero. For example, McGinnis and Foege [11] reported 3,000 alcohol-attributable deaths from stomach cancer for 1995, but Midanik et al. [12] reported none in 2001. On the other hand, Midanik et al. reported nearly 7,000 deaths from mental, nervous system, and neuromuscular disorders, while McGinnis and Foege reported none. The earlier study included 4,000 deaths from pneumonia and inﬂuenza and 3,000 deaths from diabetes, while the more recent report had no alcohol-attributable deaths in those categories. The absence of ICD codes identifying speciﬁc conditions in these studies suggests that some of these differences may reﬂect category assignment discrepancies (e.g., alcohol use disorders, toxicity/ overdose), but others more clearly reﬂect differences in the conditions included as causally related to alcohol consumption. Further scrutiny reveals important differences in the numbers of deaths reported in the categories in which both reports count some deaths. Of particular note is the difference in deaths from digestive diseases, which are reported at 20,223 by Midanik et al. for 2001 but only 7,900 by McGinnis and Foege for 1995, with the discrepancy reﬂecting a threefold difference in the chronic liver disease category (almost 19,000 in one study vs. 6,000 in the other). As noted, it seems unlikely that both sets of ﬁndings could be correct, given the magnitude of the differences, the relatively short time period separating the two studies, and the fact that per capita alcohol consumption changed by less than 2% during that time [13]. The more plausible conclusion is that differences in data and methodology account for the differences in the composition of

Table 1. Alcohol-attributed mortality from two US studies

Measuring Health Consequences of Alcohol Consumption

Dig Dis 2005;23:162–169

Cause of death

McGinnis and Foege [11]

Chronic conditions Cancers Stomach cancer 3,000 Liver cancer 1,500 Oropharyngeal cancer 3,000 Esophageal cancer 4,500 Laryngeal cancer 800 Breast cancer 0 Prostate cancer 0 Circulatory diseases Stroke 11,000 Hypertension 3,000 Alcoholic cardiomyopathy 0 Ischemic heart disease 0 Supraventricular cardiac dysrhythmia 0 Respiratory diseases Pneumonia/inﬂuenza 4,000 Tuberculosis 300 Digestive diseases Ulcers/digestive diseases 900 Chronic liver disease 6,000 Pancreatitis 1,000 Cholelithiasis 0 Diabetes 3,000 Mental, nervous system, and neuromuscular disorders Alcohol abuse and dependence 0 Alcoholic psychosis 0 Alcoholic polyneuropathy 0 Degeneration of nervous system 0 Epilepsy 0 Alcoholic myopathy 0 Fetal and newborn effects 0 Psoriasis 0 Total, chronic conditions 42,000 Acute conditions Injuries – unintentional Motor vehicle Fire injuries Fall injuries Water, aviation injuries Other unintentional injuries Injuries – intentional Homicide Suicide Toxicity/overdose Total, acute conditions Total

Midanik et al. [12]

0 690 360 447 233 352 233 2,401 1,221 499 908 165 0 0 107 18,926 1,261 0 0 5,841 742 3 114 177 2 152 0 34,833

17,000 1,000 5,000 1,500 0

14,109 1,167 4,766 1,071 570

10,000 8,500 20,000 63,000

7,957 6,995 4,297 40,933

105,000

75,766

165

estimated alcohol-attributable mortality between these two studies. Both of these studies have been conducted by highly respected researchers using broadly similar methods and relying on published ﬁndings and ofﬁcial vital statistics. The methods involve application of population-attributable fractions for alcohol (i.e., AAFs) to cause-speciﬁc data on deaths by age and sex. The studies differ in the sources and values of the AAFs employed. Differences in the conditions included (i.e., for which only one of the two studies employed an AAF of 10) and differences in the AAF values assigned to conditions that are included in both studies are clearly the primary source of the differences in reported mortality. An important effect of these differences is to leave uncertainty as to whether and how overall alcohol-attributable mortality may have changed over the period between the two studies. Signiﬁcant variation in included conditions across studies is more the norm than the exception. A recent study found substantial differences in the included conditions across three major studies from the US, Canada, and Australia and, based on an extensive assessment of the epidemiologic literature in ﬁve languages published in 1995 or later, recommended a list of 47 conditions (with associated ICD-9 codes) for inclusion in studies of the social costs of alcohol (and, by extension, studies of the health-related burden of alcohol) [9]. It appears that the potential contribution of this effort to assess the full scope of conditions for which there is evidence of a causal association with alcohol consumption may have been underappreciated; efforts to quantify the health effects of alcohol consumption would beneﬁt from reference to (periodically updated) assessments of this sort. The foregoing comparison between two speciﬁc studies illustrates that scientiﬁc progress in understanding the health effects of alcohol consumption has provided our best public health researchers – and hence, the public – with changing information about which conditions are partially caused by alcohol consumption, the strength of the causal relationships involved, and the extent of resulting overall damage to health at the individual and population levels.

Methodological Issues

The lack of stable consensus regarding the health effects of alcohol consumption ultimately reﬂects the scientiﬁc challenges involved in identifying and reliably estimating such effects. Beyond gaining agreement on which condi-

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tions should be included as causally linked to alcohol consumption, the methods used in studies seeking to quantify relationships between alcohol consumption and health outcomes can have signiﬁcant effects on estimated effect sizes (e.g., magnitudes of estimated relative risk ratios). Several recent studies have identiﬁed key methodological concerns that must be addressed in epidemiologic research into the health effects of alcohol consumption [1–3, 14–16]. Among the most important issues for improving measurement of the relationships between alcohol consumption and health outcomes are the following. Selection of Appropriate Cohorts and Comparison Groups Cohorts must be reasonably representative and allow sufﬁcient variation to avoid omitting relevant aspects of the relationship between alcohol consumption and health outcomes. Comparison groups must be chosen with care as well, so that the counterfactual drinking scenario (e.g., abstinence, or drinking at a ‘safe’ level) is well speciﬁed and does not incorporate unmeasured heterogeneity. In particular, the distinction between lifetime abstainers and former drinkers should be observed in selecting a comparison group [1, 2]. Measurement of Consumption Levels and Patterns Epidemiologic analysis requires accurate measurement of the exposure in question, i.e., the relevant aspects of alcohol consumption. Different aspects of the consumption pattern (i.e., the temporal distribution of consumption of a given volume of ethanol) and drinking context (setting and surroundings, presence or absence of food, etc.) may exert critical inﬂuence on the risks for different health outcomes, and these inﬂuences may vary across population groups. An additional complicating factor is the timing of consumption relative to reported health outcomes; the appropriate time lag between observed consumption and health outcome assessment may be expected to vary across health conditions [1, 17]. Correcting for Confounding Effects The interactions among alcohol consumption levels and patterns, other health behaviors, environmental factors, and individual and demographic characteristics create complex confounding effects. Analysts must seek to correct for the full range of relevant confounders while avoiding over-correcting (which may occur when standard correction methods are applied to factors that ﬁgure in the causal chain leading from alcohol consumption to health outcomes) [2].

Bloss

Separate Reporting of Beneﬁcial and Adverse Consequences Much recent attention has focused on potential beneﬁcial effects of alcohol consumption. There is now substantial evidence of a U- or J-shaped relationship between alcohol consumption and coronary heart disease for at least some population groups [3, 5, 18, 19], and suggestive evidence that qualitatively similar associations may exist for type-2 diabetes and cholelithiasis [9, 20, 21]. When there is evidence of both adverse and beneﬁcial effects of alcohol consumption – either within or across outcome categories – it is important to document both kinds of consequences, and not simply the net balance of two competing effects. The study by Corrao et al. [16] sets a useful standard in this area by distinguishing different effects and associating each outcome with speciﬁc consumption ranges. This disaggregation provides much more information about the health effects of alcohol than if the roughly equal numbers of deaths reported as caused and prevented by low-level consumption in that study were netted against one another and reported as no overall effect on mortality. Appropriate Construction, Application, and Interpretation of AAFs Attributable fractions may be misused in a variety of ways, and the results of such misuse could lead to signiﬁcant misstatements of the health consequences of alcohol consumption [22]. Even for well-constructed attributable fractions, problems may arise when previously published fractions are applied to current vital statistics on causespeciﬁc deaths without consideration of the possibility that the fractions may change over time. Such changes could result from changes in population prevalence of drinking at particular levels or from changes in the underlying relative risks. For some outcomes, such changes may result from technological, legal, or other factors not directly related to alcohol, such as widespread use of air bags, enforcement of speed limits, or changes in health care practices. The possibility that changes in alcohol-attributable mortality could result from changes in AAFs should encourage the use of up-to-date information in estimating aggregate health effects of alcohol consumption. Recognition of Health Consequences of Drinking by Others Most of the health consequences of alcohol consumption accrue to the drinker. However, some important alcohol-attributable health outcomes may accrue to indi-

Measuring Health Consequences of Alcohol Consumption

viduals as a result of drinking by others; such effects need to be quantiﬁed and catalogued along with other health consequences of alcohol consumption. For example, in the US, 44% of decedents in crashes involving drinking drivers were persons other than the drinking drivers [23], and alcohol has been estimated to be involved in one fourth of all violent crimes [24]. Most such ‘third-party’ effects may be expected to fall in the categories of unintentional injuries, intentional injuries, and fetal alcohol effects. Identifying and measuring the effects of alcohol that result from someone else’s drinking poses special problems, both at the individual level in terms of primary observation and causal attribution and at the population level in the estimation of aggregate effects. Nevertheless, such effects represent an important component of the health consequences of alcohol consumption. Measurement of Health Outcomes Studies of the health effects of alcohol consumption most commonly assess mortality outcomes, although alcohol also has many non-fatal effects on health. Mortality is relatively easy to measure because of the dichotomous character of life/death outcomes, and the severity of these outcomes makes them obviously important. Even in the relatively straightforward case of injury outcomes, however, signiﬁcant uncertainties remain about the magnitude of alcohol involvement in injury mortality. To build on the successful model from the trafﬁc crash area and improve understanding of the role of alcohol in injury mortality from various causes, Hingson et al. [25] have called for comprehensive testing of all injury deaths for alcohol involvement. For mortality from all causes, the need for additional research to clarify the risk relationships associated with various consumption behaviors and individual characteristics is manifest. Beyond mortality alone, a more complete view of the health effects of alcohol must incorporate non-fatal health consequences as well. There is credible evidence from various countries that non-fatal effects account for a signiﬁcant share of the overall health burden associated with alcohol [3, 26–28]. Full accounting of morbidity outcomes must confront a range of qualitative considerations, encompassing illness, pain, and disability, although most studies have used indicators of health care utilization (e.g., hospitalizations, hospital days, health care expenditures). Advances in measurement of healthrelated quality of life represent a particularly promising development in the measurement of non-fatal outcomes with two signiﬁcant potential beneﬁts. First, cost-effectiveness and cost-utility analyses of interventions de-

Dig Dis 2005;23:162–169

167

signed to reduce or prevent adverse health consequences are supported by broad-based measures of health-related quality of life. Second, various measures of health-related quality of life have been adapted for use in constructing summary measures of population health that combine information on mortality and impaired health into a single metric (e.g., quality-adjusted life-years, or QALYs). Summary measures of population health, including QALYs and disability-adjusted life years (DALYs) provide a framework for assessing health burden attributable to alcohol that captures a broader range of health consequences than can commonly used measures of mortality or morbidity alone [29–33]. This catalog of methodological challenges captures an important part – but only part – of the daunting range of issues to be addressed in measuring the health effects of alcohol consumption. A worthy component of the research agenda involves identifying methodological tools that can relieve some of the complexities confronting analyses of these consequences.

Conclusion

Recent results suggest both the enormous scientiﬁc progress that has been achieved in assessing health consequences of alcohol consumption and the tremendous opportunities for further discovery that lie ahead. The detailed information on health outcomes, and the ability to discern with reasonable precision the role of alcohol as an underlying cause in a wide variety of conditions, attests to the quality and quantity of scientiﬁc progress in this area. As in other areas, the reward for scientiﬁc prog-

ress is often a broader set of questions and a greater sense of what is not known, and that is certainly the case with alcohol and health. Missing from our knowledge is a ﬁnegrained understanding of the mechanisms of underlying risk for many chronic conditions caused by alcohol, and a resulting lack of knowledge about exactly who is at risk or which speciﬁc behaviors contribute most to risk. This stands in contrast to many acute outcomes, for which the mechanism of risk is known to be the effect of intoxication in contexts where poor judgment and erratic behavior culminate in injuries. In these cases, the causal link between alcohol consumption and outcomes is conceptually clear, yet reliable measures of the extent of alcohol involvement in many categories of injuries are still lacking. Sustained documentation of the role of alcohol in trafﬁc crash injuries over 25 years has led to a rich understanding of the causal role of alcohol in a public health tragedy, and public attention and action has led to signiﬁcant reductions in alcohol-related trafﬁc deaths. For the full range of health consequences of alcohol consumption, among the greatest needs is for information on trends, both at an overall level and at the level of individual conditions. A range of methodological challenges must be addressed to establish a reporting basis that will allow assessment of changes over time in health consequences attributable to alcohol. Valid comparisons over time are needed to facilitate identiﬁcation of areas where improvements in public health may be occurring or may be most needed, to support evaluation of speciﬁc interventions, and to encourage public awareness of the extent and seriousness of alcohol problems that is an essential prerequisite to changing attitudes and behaviors involving alcohol consumption.

References 1 Rehm J, Gmel G, Sempos CT, Trevisan M: Alcohol-related morbidity and mortality. Alcohol Res Health 2003;27:39–51. 2 Rehm J, Gmel G: Alcohol consumption and total mortality/morbidity – deﬁnitions and methodological implications. Best Pract Res Clin Gastroenterol 2003;17:497–505. 3 English DR, Holman CDJ, Milne E, Winter MG, Hulse GK, Codde JP, Bower CI, Corti B, Dawes V, de Klerk N, Knuiman MW, Kurinczuk JJ, Lewin GF, Ryan GA: The Quantiﬁcation of Drug Caused Morbidity and Mortality in Australia, 1995 edition. Canberra, Commonwealth Department of Human Services and Health, 1995.

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4 Corrao G, Bagnardi V, Zambon A, La Vecchia C: A meta-analysis of alcohol consumption and the risk of 15 diseases. Prev Med 2004;38:613– 619. 5 Ridolfo B, Stevenson C: The Quantiﬁcation of Drug-Caused Mortality and Morbidity in Australia 1998. Canberra, Australian Institute of Health and Welfare, 2001. 6 National Institute on Alcohol Abuse and Alcoholism: Helping Patients Who Drink Too Much: A Clinician’s Guide. 05-3769. Bethesda, US Department of Health and Human Services, National Institutes of Health, 2005. 7 Dawson DA, Grant BF, Li TK: Quantifying the risks associated with exceeding recommended drinking limits. Alcohol Clin Exp Res 2005;29:902–908.

8 US Centers for Disease Control and Prevention: Alcohol-Related Disease Impact (ARDI). http://apps.nccd.cdc.gov/ardi/Homepage. aspx. 2005. 9 Gutjahr E, Gmel G: Deﬁning alcohol-related fatal medical conditions for social-cost studies in Western societies: An update of the epidemiological evidence. J Subst Abuse 2001; 13: 239–264. 10 Stinson FS, Nephew TM: State Trends in Alcohol-Related Mortality, 1979–1992. 96-4174. US Alcohol Epidemiologic Data Reference Manual, vol 5. Bethesda, US Department of Health and Human Services, National Institute on Alcohol Abuse and Alcoholism, 1996.

Bloss

11 McGinnis JM, Foege WH: Mortality and morbidity attributable to use of addictive substances in the United States. Proc Assoc Am Physicians 1999;111:109–118. 12 Midanik LT, Chaloupka FJ, Saitz R, Toomey TL, Fellows JL, Dufour M, Landen M, Brounstein PJ, Stahre MA, Brewer RD, Naimi TS, Miller JW: Alcohol-attributable deaths and years of potential life lost – United States, 2001. MMWR Morb Mortal Wkly Rep 2004; 53:866–870. 13 Lakins NE, Williams GD, Yi H-Y, Smothers BA: Apparent Per Capita Alcohol Consumption: National, State, and Regional Trends, 1977–2002. Surveillance Report No. 66. Bethesda, National Institute on Alcohol Abuse and Alcoholism, 2004. 14 Rehm J, Sempos CT, Trevisan M: Average volume of alcohol consumption, patterns of drinking and risk of coronary heart disease – a review. J Cardiovasc Risk 2003;10:15–20. 15 Gutjahr E, Gmel G, Rehm J: Relation between average alcohol consumption and disease: An overview. Eur Addict Res 2001;7:117–127. 16 Corrao G, Rubbiati L, Zambon A, Arico S: Alcohol-attributable and alcohol-preventable mortality in Italy – a balance in 1983 and 1996. Eur J Public Health 2002;12:214–223. 17 Rehm J, Room R, Graham K, Monteiro M, Gmel G, Sempos CT: The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease: an overview. Addiction 2003;98:1209–1228. 18 Mukamal KJ, Rimm EB: Alcohol’s effects on the risk for coronary heart disease. Alcohol Res Health 2001;25:255–261.

Measuring Health Consequences of Alcohol Consumption

19 Corrao G, Rubbiati L, Bagnardi V, Zambon A, Poikolainen K: Alcohol and coronary heart disease: a meta-analysis. Addiction 2000; 95: 1505–1523. 20 Ashley MJ, Rehm J, Bondy S, Single E, Rankin J: Beyond ischemic heart disease: are there other health beneﬁts from drinking alcohol? Contemp Drug Probl 2000;27:735–777. 21 Koppes LLJ, Dekker JM, Hendriks HFJ, Bouter LM, Heine RJ: Moderate alcohol consumption lowers the risk of type 2 diabetes – a metaanalysis of prospective observational studies. Diabetes Care 2005;28:719–725. 22 Rockhill B, Newman B, Weinberg C: Use and misuse of population attributable fractions. Am J Public Health 1998;88:15–19. 23 Hingson R, Winter M: Epidemiology and consequences of drinking and driving. Alcohol Res Health 2003;27:63–78. 24 Greenfeld LA: Alcohol and Crime: An Analysis of National Data on the Prevalence of Alcohol Involvement in Crime. Washington, US Department of Justice, Ofﬁce of Justice Programs, 1998. 25 Hingson R, Swahn M, Sleet DA: Prevention of alcohol-related injuries; in Doll L, Mercy J, Bonzo S, Sleet D (eds): Handbook of Injury and Violence Prevention. New York, Springer, 2006. 26 Harwood H, Fountain D, Livermore G: The Economic Costs of Alcohol and Drug Abuse in the United States 1992. NIH Publication No. 98-4327. Report prepared for the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, US Department of Health and Human Services. Rockville, National Institutes of Health, 1998.

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27 Single E, Robson L, Rehm J, Xie X: Morbidity and mortality attributable to alcohol, tobacco, and illicit drug use in Canada. Am J Public Health 1999;89:385–390. 28 Rehm J, Room R, Monteiro M, Gmel G, Graham K, Rehn N, Sempos CT, Frick U, Jernigan D: Alcohol use; in Ezzati M, Lopez AD, Rodgers A, Murray CJL (eds): Comparative Quantiﬁcation of Health Risks: Global and Regional Burden of Disease Attributable to Selected Major Risk Factors. Geneva, World Health Organization, 2004, pp 959–1108. 29 Green C, Brazier J, Deverill M: Valuing healthrelated quality of life – a review of health state valuation techniques. Pharmacoeconomics 2000;17:151–165. 30 Gold MR, Stevenson D, Fryback DG: HALYs and QALYs and DALYs, oh my: similarities and differences in summary measures of population health. Annu Rev Public Health 2002; 23:115–134. 31 Russell LB, Gold MR, Siegel JE, Daniels N, Weinstein MC: The role of cost-effectiveness analysis in health and medicine. JAMA 1996; 276:1172–1177. 32 McKenna MT, Michaud CM, Murray CJL, Marks JS: Assessing the burden of disease in the United States using disability-adjusted life years. Am J Prev Med 2005;28:415–423. 33 Murray CJL, Salomon JA, Mathers C: A critical examination of summary measures of population health. Bull World Health Organ 2000; 78:981–994.

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we will not give a general review here, but will restrict ourselves to moderate consumption, using three main models of disease etiology: (1) average moderate alcohol consumption is causative of disease (positive or negative effect); (2) average moderate alcohol consumption plus other moderating factors are causative of disease, and (3) average moderate alcohol consumption plus heavy episodic (‘binge’) drinking are causative of disease.

Average moderate alcohol consumption is deﬁned here as using between 10 and 40 g/day. In trying to summarize the literature in this ﬁeld, conditions known to be associated with alcohol are explored in detail with respect to moderate drinking, and possible explanations are given when available.

Methods

Table 1. Diseases of the gastrointestinal system causally associated

with high alcohol intake and deﬁned as ‘alcoholic’ diseases, by ICD10 code Organ

Condition

ICD-10

Liver

Alcoholic liver diseases Alcoholic fatty liver Alcoholic hepatitis Alcoholic ﬁbrosis and sclerosis of the liver Alcoholic cirrhosis of the liver Alcoholic cirrhosis NOS Alcoholic hepatic failure Alcoholic hepatic failure: Nitric oxide synthase Acute Chronic Subacute With or without hepatic coma Alcoholic liver disease, unspeciﬁed Alcoholic gastritis Alcohol-induced chronic pancreatitis

K70 K70 K70.1 K70.2 K70.3

Stomach Pancreas

Table 2. Conditions of the gastrointestinal system by ICD code1 found to be causally associated with alcohol consumption in a large meta-analysis [1, 6, 48]

Diseases that are, in general, considered to be causally related to alcohol consumption were identiﬁed from peer-reviewed metaanalyses and are shown in tables 1 and 2. Since many of the risk estimates increase with consumption, the most recent relevant literature identiﬁed using the Medline search engine was checked to identify associations with moderate drinking in both single studies and other meta-analyses.

K70.4

Search Strategy and Criteria for Inclusion/Exclusion Articles included in this review were identiﬁed from searches of the National Library of Medicine’s PubMed database and the OVID Medline database from 1966 to June, week 1, 2005. The main search terms used were: ‘alcohol drinking’ or ‘moderate drinking’ in combination with each of the identiﬁed disease categories using their MeSH subject headings (for example, for liver cancer, ‘liver neoplasms’ was used). In order not to miss any articles from speciﬁc disease categories, the search was sometimes cast more widely, and hand searches of included articles were also checked. Only English articles were selected for further review.

K70.9 K29.2 K86.0

Article Inclusion Criteria Articles included were case-control or cohort studies (or metaanalyses of these) with data on the effects of alcohol consumption either as a main or secondary ﬁnding. Estimates of risk were pre-

Organ

Condition

ICD-9

ICD-10

Mouth Esophagus

Oropharyngeal cancer Esophageal cancer Esophageal varices Gastroesophageal hemorrhage Alcoholic gastritis Liver cancer Alcoholic liver cirrhosis Unspeciﬁed liver cirrhosis Acute pancreatitis Chronic pancreatitis Chronic pancreatitis (alcohol induced) Cholelithiasis (gallstones)

141, 143–6, 148–9 150 456.0–456.2 530.7 535.3 155 571.0–571.3 571.5–571.9 577.0 577.1

C00–C14 C15 I85 K22.6 K29.2 C22 K70.3 K74.6 K85 K86.1 K86.0 K80

Stomach Liver

Pancreas

Gall bladder

574

1

In addition, we checked references of conditions, which had been discussed causally related with alcohol consumption, even though the relationship has not been conclusive. These included cancers of the stomach, bladder, colon and rectum, peptic ulcer, esophagitis, and Barrett’s esophagus [23].

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171

Patterns of drinking

Average volume

Intoxication Toxic and benefical biochemical effects✽

Fig. 1. Conceptual model of alcohol con-

sumption, intermediate mechanisms and long-term consequences. * Independent of intoxication or dependence. From Rehm et al. [4].

Chronic disease

sented when at all possible, either as odds ratios or relative risks between exposed and unexposed groups, and for each level of drinking. To be included in the review, articles also had to report the number of cases and non-cases included in the study.

Alcohol and the GI Tract in Brief

Ethanol is absorbed throughout the length of the GI tract by simple diffusion [9]. Alcohol dehydrogenase is the main enzyme involved in initial metabolism of alcohol and has been found throughout the GI tract [10]. Of clinical importance, however, are the breakdown products of alcohol metabolism, speciﬁcally acetaldehyde, a known toxic compound in the body. It is thought that this compound is the one responsible for many of the harms in the GI tract, most notably in the liver [11]. Exposure to alcohol in the small and large intestine may also create a number of problems for absorption and excretion of other nutrients, including vitamins A, D, E, K [9], B12 [12], and folate [13], among others. The relationship between alcohol and health and other consequences is complex. Figure 1 illustrates how the relationship works through three intermediate mechanisms, one of which will be looked at in-depth here: direct toxic and biological effects. This term is used to summarize all the biochemical effects of alcohol on body functions other than intoxication and dependence.

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Dependence

Accidents/injuries (acute disease)

Acute social

Chronic social

Moderate Drinking and Disease

All relative risks cited in this text are summarized in table 3. Mouth Oropharyngeal cancer has been associated with alcohol in a dose-response manner in both single studies and large meta-analyses. In a meta-analysis of 8 studies by Corrao et al. [14] in the late 1990s, it was reported that the risk of disease increased about twofold in moderate drinkers (25 g/day) compared to non-drinkers. This conﬁrmed an earlier hypothesis by Doll et al. [15] who likewise reported a positive dose-response relationship with oropharyngeal cancer. Recently, a meta-analysis investigating the etiology of a number of aerodigestive cancers found that moderate alcohol consumption of less than 4 drinks/day was associated with a relative risk of between 1.5 and 1.7 compared to non-drinkers [16]. Although this relationship may not be exactly linear, no J-shaped association indicating protection of moderate drinking was evident in further analysis [14], indicating a possible threshold effect for lower alcohol consumption. Esophagus Esophageal cancer also has a well-established relationship with alcohol consumption in epidemiological studies [17]. Although ﬁrst reported for excessive alcohol con-

Taylor /Rehm /Gmel

Table 3. Summary of risk estimates for moderate average consumption of alcohol and causally related diseases of the gastrointestinal tract

Condition

RR (range of risk for different risk groups or pooled analysis)

Oropharyngeal cancer

1.9–2.2 [14] 1.5–1.7 [16] 1.45 [3] 1.5–1.6 [14] 1.5 [16] 1.8 [3] 1.6–3.0 [14] 1.26 [3] 0.47 (RR for H. pylori infection only) 1.2 [14] 1.6–3.0 [14]

Esophageal cancer

Esophageal varices Alcoholic gastritis

Liver cancer Alcoholic liver cirrhosis Unspeciﬁed liver cirrhosis Acute pancreatitis Chronic pancreatitis Cholelithiasis (gallstones)

1.26 [3] 1.3 [14] 1.3 [14] 0.82 [1] 0.6–0.8

Comments

Complication of liver cirrhosis, same risk estimate H. pylori is causative of gastritis, RR may not be applicable to gastritis directly May be dependent on consumption patterns May be dependent on consumption patterns

sumption in 1962 [18], risk is now well established for smaller quantities of drinking through larger epidemiological studies and subsequent meta-analyses controlling for confounding factors such as smoking [19, 20]. In a metaanalysis by Longnecker and Enger [19], the authors showed that the risk of esophageal cancer increases by about 30% with each additional daily drink, and no protective effect of moderate consumption is apparent. As well, in a large multi-study report, Zeka et al. [16] showed that even moderate levels (0–4 drinks/day) of consumption were signiﬁcantly associated with modest risk increases of about 50% compared to non-drinkers. In addition, there appears to be a synergistic (multiplicative) effect of alcohol consumption and smoking, but this relationship increased multiplicatively with increases in alcohol and smoking status. It has been proposed that alcohol exposure makes the mucosa lining the esophagus more susceptible to damage and inﬂammation, and thus vulnerability to carcinogens created by the breakdown of ethanol [21, 22]; however, this has been mostly studied in alcoholics. Esophagitis and Barrett’s esophagus are both conditions associated with alcohol use, but the literature is not conclusive [23]. There is some clinical evidence of a relationship with heavy drinking, but systematic studies on moderate alcohol consumption and these conditions are lacking.

Stomach Alcohol may be related to gastritis and a relationship with stomach cancer has been proposed but not systematically proven [1, 23, 24]. Alcohol has been associated with Helicobacter pylori infection in some studies, which may cause an inﬂammatory disease of the gastric mucosa [25]. Brenner et al. [26] showed an inverse relationship between alcohol consumption and H. pylori infection, indicating that lowmoderate alcohol consumption of wine in particular may have some protective effects, showing an odds ratio of 0.47 (0.26–0.88) compared to non-drinkers. However, consistently proven results for the associated conditions of H. pylori infection such as gastritis have not been shown. Wine has also been shown to possess antimicrobial actions against Escherichia coli, Salmonella, and Shigella, so it may provide some protection against infection with these agents [27]. H. pylori infection may also be associated with stomach cancer [28], although its inclusion previously has been controversial [29]. Summarizing the current research, there are no conclusive indications for a causative role of alcohol in stomach cancer [1, 23, 24].

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173

Liver Alcohol’s relationship with liver diseases is well established. Before this is discussed with respect to moderate alcohol consumption, however, a brief description of liver disease is warranted. Alcohol-related liver disease covers a number of hepatic conditions, mainly fatty liver, hepatitis, and cirrhosis [29–31]. Deposition of fat in the liver is very common in alcoholics. Chronic alcoholics may also develop increases in collagen in their liver, causing ﬁbrosis and steatosis due to persistent damage. Furthermore, chronic alcohol use can result in hepatocellular necrosis and inﬂammation that characterizes hepatitis and cirrhosis. Probably the most well known of all the diseases related to alcohol and alcohol abuse is cirrhosis of the liver. It has been extensively studied, and the ﬁndings are consistent – alcohol has a negative relationship with cirrhosis that increases as alcohol intake and duration of exposure increase. The meta-analysis of 8 studies by Corrao et al. [14] found a pooled relative risk estimate of between 1.6 and 3.0 for moderate drinkers (!25 g/day) compared to non-drinkers. These estimates included men and women and controlled for a number of important covariates. In addition, moderate alcohol consumption may promote at-risk groups for developing liver cirrhosis compared to non-drinking groups. In a paper by Westin et al. [32], moderate alcohol intake increased ﬁbrosis progression in patients with preexisting hepatitis C, though not at as high a rate as heavier drinkers. One of the most accepted ﬁndings in alcohol epidemiology is the relationship of high alcohol intake and diseases of the liver, including liver cancer [24, 33]. Moderate drinking does not appear to have any beneﬁcial effects on liver cancer at all. Corrao et al. [14], in their metaanalysis, found that even moderate doses of 25 g/day resulted in an elevated risk of liver cancer in both men and women, although it was a small increase. Donato et al. [34] investigated the dose response of alcohol and liver cancer but found slightly different results, where the odds of cancer were not signiﬁcantly increased for either men or women consuming !80 g/day. Though it is a ﬁrm consensus that alcohol plays a role in liver disease (fatty liver, liver cancer, hepatitis, liver cirrhosis) the pathogenesis is not yet fully understood. Rodes et al. [30] state that alcoholic liver disease is rarely found without phases of preceding excessive use, which has been seen developing even after 12 months of abstinence. It might be that effects of moderate average alcohol use may just mask effects of intermittent heavy use phases. Currently, there is growing evidence that patterns

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of drinking (e.g. excessive drinking phases) may better model the liver disease incidence than the long-standing theory of cumulative amounts. For example Sorensen et al. [31] showed that among alcoholics the development of liver cirrhosis was independent of the duration of excessive drinking prior to entering the study. Previous reports have linked the role of patterns of drinking with disease outcomes and burden of disease [4, 30]. However, this area of research is still in its relative infancy and use of well-accepted standards and deﬁnitions in systematic studies is needed [4]. Esophageal varices are dilated blood vessels in the esophagus and are usually secondary to alcoholic liver damage [35]. Patients who develop cirrhosis tend to have decreased blood ﬂow through the liver, resulting in increases of blood ﬂow in blood vessels surrounding the esophagus, potentially becoming so engorged with blood that they rupture. Because of the relationship with liver damage, esophageal varices are usually modelled as having the same risk estimates as liver cirrhosis, between 1.6 and 3.0 for moderate drinkers (!25 g/day) compared to non-drinkers. Pancreas The relationship between alcohol consumption and acute pancreatitis has been shown to display a dose-response relationship with alcohol [36, 37]. However, recent reviews have pointed to a tenuous relationship between alcohol and pancreatitis, citing previous bouts of pancreatitis, genetic factors and its undetermined associations with chronic pancreatitis [38, 39]. Chronic pancreatitis has also been linked to alcohol abuse, but the role of moderate alcohol use is unclear. In a study of non-alcoholic chronic pancreatitis, Lankisch et al. [40] showed that alcohol consumption of !50 g/day tended to accelerate the disease process, and in some cases increased the severity, just as higher alcohol consumption did. The pooled relative risk for chronic pancreatitis was found to be 1.3 (1.2–1.5) for drinkers of 25 g/day compared to non-drinkers [14]. Gall Bladder There is evidence that moderate alcohol use exerts a protective effect with respect to gallstones. Lower risk of gallstones among moderate drinkers compared to nondrinkers has been replicated in past studies typically showing relative risk estimates between 0.6 and 0.8 [41– 44]; however, there are a number of other hypotheses for this. It has been speculated that symptoms of gallstones may affect a patient’s alcohol consumption, and the pro-

Taylor /Rehm /Gmel

tective effect of alcohol disappeared when this was controlled for in past studies [45]. However, a number of large meta-analyses in the mid-1990s concluded that there is enough evidence to infer a causal protective relationship between alcohol consumption and gallstones, with a pooled relative risk estimate of 0.82 (0.76–0.90) for both men and women [1]. Among certain GI diseases, no alcohol is recommended. In patients with liver cirrhosis with co-infection with hepatitis C or HIV, alcohol is not recommended in any dose for patients in therapy due to increased progression of disease and interactions with agents used in treatment of these diseases [46].

Conclusions

Moderate volumes of alcohol consumption have been shown in this review to play a role in GI disease etiology, both positively and negatively. However, the average volume of consumption is not the only factor at work in alcohol-related disease epidemiology. Another major determinant of health risk is associated with patterns of drinking (such as heavy episodic drinking or ‘binge drinking’) [7]. However, clear deﬁnitions of patterns of drinking, lack of standardized exposure measures, and limited use in cohort and case-control studies adequate for metaanalysis are problem areas in this research [4, 6]. The potential impact of patterns is even more important, as even among alcoholics, it has been found to be important to be able to distinguish between heavy episodic drinking and other types. In a study of alcoholic patients, Wetterling et al. [47] found that distinctions must be made between: (1) continuous drinkers = almost daily consumption without binges; (2) frequent heavy drinkers = frequent alcohol consumption (more than three times/week) with binges more than once a week, and (3) episodic drinkers = longer sober periods, some binges, but less than once per week. The authors found that, among other non-GI diseases, pancreatitis and esophageal varices were more frequent among heavy drinkers than among episodic drinkers, indicating effects of long-term exposure. Heavy drinkers also had more upper GI disorders, although their estimated lifetime alcohol intake was comparable to that of continuous drinkers [47]. As more and more research is appearing on patterns of drinking and their role in causing disease, it may turn out that eventually many detrimental effects of moderate consumption will actually be attributable to episodic binge drinking. Such effects in the past showed up in the

Moderate Alcohol Consumption and the Gastrointestinal Tract

average moderate consumption category due to averaging for people who consume with little or no alcohol on no bingeing days. As many of the traditional medical epidemiological studies have not controlled for binge drinking episodes, this alternative explanation can currently not be excluded. Moderate alcohol consumption plays a role in many of the well-accepted alcohol-related GI diseases, although the relationship is not as well known, or necessarily as clinically relevant, as that of excessive consumption. However, since the majority of those consuming alcohol do so at moderate levels [6], it is important to know the impact of social drinking on health, whether it is positive or negative. Moderate drinking has been shown to have a positive effect on gallstone disease, H. pylori infection, and some enteric pathogens, although more studies must be completed in order to fully understand what the reduction in risk is. From a public health point of view, the role of moderate drinking causing GI diseases has to be seen in perspective with other disease consequences. In this perspective, the overall balance seems to be positive, mainly due to the cardioprotective effects of alcohol [6]. Again, this effect is conﬁned to speciﬁc patterns of drinking, especially the avoidance of heavy drinking episodes [48]. In sum, moderate drinking entails risks and beneﬁts for disease, but if average moderate drinking can be established as a prevailing drinking style without any heavy drinking episodes, the overall health balance may be positive. Unfortunately, such a drinking style of moderate consumption without any heavy drinking episodes is very rare around the world [49]. If one shifts the focus from public health to the individual, the risk proﬁle for moderate drinking may be different based on genetic predisposition and lifestyle, and thus, no general recommendations can be given here.

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16 Zeka A, Gore R, Kriebel D: Effects of alcohol and tobacco on aerodigestive cancer risks: a metaregression analysis. Cancer Causes Control 2003;14:897–906. 17 Enzinger PC, Mayer RJ: Esophageal cancer. N Engl J Med 2003;349:2241–2252. 18 Schwarts D, Lellouch J, Flamant R, et al: Alcohol and cancer. Results of a retrospective investigation. Rev Fr Etud Clin Biol 1962; 7: 590–596. 19 Longnecker MP, Enger SM: Epidemiologic data on alcoholic beverage consumption and risk of cancer. Clin Chim Acta 1996;246:121– 141. 20 Engel LS, Chow WH, Vaughan TL, et al: Population attributable risks of esophageal and gastric cancers. J Natl Cancer Inst 2003; 95: 1404–1413. 21 Blot WJ: Alcohol and cancer. Cancer Res 1992; 52(suppl):2119s–2131s. 22 Seitz HK, Poschl G: The role of gastrointestinal factors in alcohol metabolism. Alcohol Alcohol 1997;32:543–549. 23 Teyssen S, Singer MV: Alcohol related diseases of the oesophagus and stomach. Best Pract Res Clin Gastroenterol 2003;17:557–573. 24 International Agency for Research on Cancer: Alcohol Drinking. IARC Monographs on the Evaluation of the Carcinogenic Risks to Human. Lyon, IARC, 1988, pp 153–246. 25 NIH Consensus Conference: Helicobacter pylori in peptic ulcer disease. NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease. JAMA 1994;272:65–69. 26 Brenner H, Bode G, Adler G, et al: Alcohol as a gastric disinfectant? The complex relationship between alcohol consumption and current Helicobacter pylori infection. Epidemiology 2001;12:209–214. 27 Weisse ME, Eberly B, Person DA: Wine as a digestive aid: comparative antimicrobial effects of bismuth salicylate and red and white wine. BMJ 1995;311:1657–1660. 28 Huang JQ, Sridhar S, Chen Y, et al: Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology 1998;114:1169–1179. 29 Salspuro MP: Alcohol consumption and cancer of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2003;17:679–694. 30 Rodes J, Salaspuro M, Sorensen TIA: Alcohol and liver disease; in Macdonald I (ed): Health Issues Related to Alcohol Consumption. Oxford, Blackwell, 1999, pp 395–450. 31 Sorensen TI, Orholm M, Bentsen KD, et al: Prospective evaluation of alcohol abuse and alcoholic liver injury in men as predictors of development of cirrhosis. Lancet 1984;ii:241– 244. 32 Westin J, Lagging LM, Spak F, et al: Moderate alcohol intake increases ﬁbrosis progression in untreated patients with hepatitis C virus infection. J Viral Hepat 2002;9:235–241. 33 Lieber CS: Alcohol and the liver: 1994 update. Gastroenterology 1994;106:1085–1105.

34 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: 323–331. 35 Bujanda L: The effects of alcohol consumption upon the gastrointestinal tract. Am J Gastroenterol 2000;95:3374–3382. 36 Talamini G, Bassi C, Falconi M, et al: Alcohol and smoking as risk factors in chronic pancreatitis and pancreatic cancer. Dig Dis Sci 1999; 44:1303–1311. 37 Apte MV, Wilson JS, Korsten MA: Alcoholrelated pancreatic damage: mechanisms and treatment. Alcohol Health Res World 1997;21: 13–20. 38 Gullo L, Migliori M, Brunetti MA, et al: Alcoholic pancreatitis: new insights into an old disease. Curr Gastroenterol Rep 2005;7:96–100. 39 Whitcomb DC: Genetic predisposition to alcoholic chronic pancreatitis. Pancreas 2003; 27: 321–326. 40 Lankisch MR, Imoto M, Layer P, et al: The effect of small amounts of alcohol on the clinical course of chronic pancreatitis. Mayo Clin Proc 2001;76:242–251. 41 La Vecchia C, Decarli A, Ferraroni M, et al: Alcohol drinking and prevalence of self-reported gallstone disease in the 1983 Italian National Health Survey. Epidemiology 1994; 5: 533– 536. 42 La Vecchia C, Negri E, D’Avanzo B, et al: Risk factors for gallstone disease requiring surgery. Int J Epidemiol 1991;20:209–215. 43 Leitzmann MF, Giovannucci EL, Stampfer MJ, et al: Prospective study of alcohol consumption patterns in relation to symptomatic gallstone disease in men. Alcohol Clin Exp Res 1999;23:835–841. 44 Misciagna G, Leoci C, Guerra V, et al: Epidemiology of cholelithiasis in southern Italy. Part II: Risk factors. Eur J Gastroenterol Hepatol 1996;8:585–593. 45 Thijs C, Knipschild P, Leffers P: Does alcohol protect against the formation of gallstones? A demonstration of protopathic bias. J Clin Epidemiol 1991;44:941–946. 46 Neuman MG, Rehm J: Alcohol, infectious disease and liver cirrhosis: implications for therapy of HIV and hepatitis C viral infections. 2005, in press. 47 Wetterling T, Veltrup C, Driessen M, et al: Drinking pattern and alcohol-related medical disorders. Alcohol Alcohol 1999;34:330–336. 48 Rehm J, Sempos CT, Trevisan M: Average volume of alcohol consumption, patterns of drinking and risk of coronary heart disease – a review. J Cardiovasc Risk 2003;10:15–20. 49 Rehm J, Rehn N, Room R: The global distribution of average volume of alcohol consumption and patterns of drinking. Eur Addict Res 2003; 9:147–156.

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for liver cancer, ‘liver neoplasms’ was used). In order not to miss any articles from speciﬁc disease categories, the search was sometimes cast more widely, and hand searches of included articles were also checked. Only English articles were selected for further review. Article Inclusion Criteria Articles included were all those with data on speciﬁc biochemical pathways in alcohol-related diseases. This was sometimes in human studies or animal model experiments, or reviews of both.

Alcohol and the GI Tract

Alcohol passes through all parts of the GI tract during moderate consumption. It is absorbed and metabolized throughout its length, and thus ethanol and its by-products exert their action in all parts of this system. It can do this via direct, local effects or systemic action of both ethanol itself and the effect of ethanol metabolites. It is important to note that the processes described in this article occur simultaneously and in conjunction with other biochemical processes not mentioned here, so describing one process or substance as causative is inappropriate in adequately describing the true nature of things. There are three main processes that break down alcohol in the body: oxidation via alcohol dehydrogenase; oxidation via the cytochrome P450 pathway, and the fatty acid-catalase system [9]. In moderate alcohol consumption, ethanol oxidation by alcohol dehydrogenase is the main system used, with the other two only joining in during chronic or acute ethanol ingestion. This review will mainly be limited to the effects of ethanol alone and the metabolites of the alcohol dehydrogenase system.

The Role of Ethanol

Ethanol is not, in and of itself, a major cell-damaging agent or carcinogenic. However, it may promote cancercausing agents through its local effects or effects of its metabolites. Locally, ethanol has been found to increase the risk of oropharyngeal cancer through injury to mucosal membranes and tissues [10], which can promote accelerated and unregulated cell proliferation, a step in carcinogenesis [11]. In addition, it has also been suggested that ethanol may also be able to act on cell membranes, allowing other carcinogenic material, such as that from tobacco smoke, into the mucous membranes [12, 13] which may reﬂect the higher risk estimate associated with smoking and drinking combined [7]. Regardless, much of

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the research to date investigating alcohol-related disease pathways all point to the effects of acetaldehyde, not pure ethanol, in mediating disease progression and cell damage.

What Is Acetaldehyde?

Acetaldehyde is the ﬁrst major breakdown product of ethanol metabolism. Ethanol is mainly metabolized in the liver by alcohol dehydrogenase and also to a lesser degree in the bowel and saliva, so acetaldehyde can be found throughout the GI tract. It is a highly reactive, toxic, and carcinogenic compound that can be very damaging. It can be effectively cleared in the liver by aldehyde dehydrogenase to non-reactive acetate, but cannot be converted as effectively in the large intestine and saliva. As a result, acetaldehyde can build up to high levels in the GI tract [14, 15], even after moderate doses [16].

Acetaldehyde as a Carcinogen

Acetaldehyde has shown itself to be a potent carcinogen in animals due to its highly reactive, toxic properties, but strong experimental evidence is lacking on its effect on humans [17], although it has been shown experimentally to display a number of destructive behaviors related to carcinogenesis. One of its most important properties is its ability to interact and bind with cellular proteins to form stable adduct molecules. It is these aldehyde-protein adducts that are believed to be responsible for the majority of cellular injury via decreased function or immune responses, but this will be explored in more detail below. Acetaldehyde is also able to bind to DNA to form adducts, which can trigger replication errors resulting in unregulated cell differentiation and proliferation [18] and unnatural exchanges of genetic material in vitro and in vivo [19, 20], both of which have been implicated in carcinogenesis. Acetaldehyde may also act on DNA by inhibiting folate metabolism [21]. Folate is an important constituent of proteins necessary for DNA synthesis and methylation. Hypomethylated DNA has been found to be associated with ethanol metabolism and alcohol-related cancers [22] and the interactions between the function of folate-related genes and alcohol consumption have also been observed to increase the risk of colorectal cancer at high doses, but actually shows some protective effects at moderate doses in the study by Sharp and Little [23].

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Animal models indicate that acetaldehyde is linked to hyperplasias in the mucosa of the upper aerodigestive tract, speciﬁcally in the nasal mucosa and larynx [24, 25]. Of the studies involving humans, there is mounting evidence that DNA damage occurs after heavy drinking situations [26–28], but this is has not been tested in moderate consumers. However, there is a strong and linear doseresponse between acetaldehyde and its carcinogenic effects, which is identical to the increasing risk of many aerodigestive cancers and alcohol consumption. The Asian Flush The Asian ﬂush, as its name suggests, is common among people of Asian descent, and is characterized by a ﬂushed face following alcohol consumption. There is evidence in some members of the Asian population that illustrates the carcinogenic effect of acetaldehyde well. 30–50% of the Asian population has a partially inactive aldehyde dehydrogenase, the enzyme responsible for the detoxiﬁcation of acetaldehyde. This results in less acetaldehyde being cleared following ethanol ingestion, and subsequently much higher levels of acetaldehyde buildup resulting in nausea, malaise, and a ﬂushed face. More signiﬁcant, however, is the substantially higher risk of aerodigestive cancers in this subpopulation. This has been studied in Japanese cancer patients, yielding an odds ratio of an over 5-fold increase in esophageal cancer among light and moderate drinkers with the inactive enzyme [29].

Acetaldehyde and Other Protein Adducts

Acetaldehyde is capable of other types of cell injury other than DNA interactions. It is able to bind well to other proteins, and preferentially to hemoglobin, albumin, tubulin, and lipoproteins [30] and attenuate their function or elicit an immune response against them. Acetaldehyde has been shown to directly damage hepatocytes via adduct formation [31, 32]. High levels of these aldehyde-protein species have been found in early alcoholic liver disease [32], and particularly in areas involved in scar tissue formation [33], intracellular protein transport [34], and effecting autoimmune responses to adduct proteins [32]. Low levels of acetaldehyde may also be able to increase preexisting disease progression. In a recent study, it was found that moderate alcohol consumption below 30 g/day can promote the progression of ﬁbrosis in patients with preexisting hepatitis C virus infection [35].

Moderate Alcohol Consumption and Diseases of the Gastrointestinal System

Another important area in ethanol metabolism, especially in the liver, is the production of reactive oxygen species, although this is less likely in moderate alcohol consumption [36]. Reactive oxygen species formed during ethanol metabolism are usually products of the cytochrome P450 system in the liver that tends to be initiated in acute alcohol toxicity and chronic alcohol abuse. Brieﬂy, reactive oxygen species are dangerous to hepatocytes and other cells because of their high reactivity. Interactions between reactive oxygen species and proteins such as enzymes render functional proteins inactive and thus more susceptible to degradation. They are able to change the properties of and destroy cell membranes due to lipid interactions, energy production through interference in mitochondria, and through direct damage to DNA [5]. The mechanisms of cellular and organ damage in the digestive system are well studied for acute and chronic heavy alcohol consumption. Moderate alcohol consumption is less studied, probably because in experimental systems, the biochemical processes are less visible and their dangerous or reactive byproducts are in far lower abundance. In fact, a very recent paper looking at blood levels of inﬂammatory markers and protein mediators found that markers such as tumor necrosis factor and cytokines and others that take part in identifying and destroying cells with acetaldehyde adducts are signiﬁcantly reduced in moderate drinkers compared to higher consumers [37]. The mechanisms described in this article occur at even small volumes of consumption, as all ethanol that is metabolized will produce acetaldehyde. Unlike chronic abuse, however, the liver-metabolizing enzymes are not saturated, thus the body is able to utilize the protective mechanisms efﬁciently in order to keep cellular damage to a minimum.

Conclusions

Ethanol and its metabolites, speciﬁcally acetaldehyde, are primarily responsible for much of the cellular damage associated with alcohol consumption. Both are related to digestive cancers and other organ damage. Primarily, acetaldehyde is involved in forming protein adducts with cellular proteins and DNA. The amount of damage tends to follow a dose-response relationship and thus, for moderate drinkers, the risk of alcohol-related diseases is much less than for chronic abusers. Three main categories of drinking exist with different risk estimates of GI-related harm: (1) chronic abuse with its clear association with GI

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harm; (2) moderate drinking with occasional acute heavy consumption (bingeing) episodes has at least some indications of harm, and (3) moderate drinking without any heavy consumption episodes has the least evidence of consequences for the GI tract, and some indirect evidence of harm.

Given this overall situation, it is recommended that for lowest risk of alcohol-related digestive diseases, alcohol consumption should be zero. However, for considerations of all-cause mortality including cardiovascular consequences, moderate consumption without any heavy drinking episodes seems to be the drinking pattern with the best risk proﬁle [38, 39].

References 1 Taylor BJ, Rehm JT, Gmel G: Moderate alcohol consumption and the gastrointestinal tract. Dig Dis 2005;23:170–176. 2 Salaspuro MP: Alcohol consumption and cancer of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 2003;17:679–694. 3 Teyssen S, Singer MV: Alcohol-related diseases of the oesophagus and stomach. Best Pract Res Clin Gastroenterol 2003; 17: 557– 573. 4 Bujanda L: The effects of alcohol consumption upon the gastrointestinal tract. Am J Gastroenterol 2000;95:3374–3382. 5 Wu D, Cederbaum AI: Alcohol, oxidative stress and free radical damage. Alcohol Res Health 2003;27:277–284. 6 Corrao G, Bagnardi V, Zambon A, Arico S: Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction 1999;94:1551–1573. 7 Zeka A, Gore R, Kriebel D: Effects of alcohol and tobacco on aerodigestive cancer risks: a metaregression analysis. Cancer Causes Control 2003;14:897–906. 8 International Agency for Research on Cancer: Alcohol Drinking. IARC Monographs on the Evaluation of the Carcinogenic Risks to Human. Lyon, International Agency for Research on Cancer, 1988, pp 15–246. 9 Cunningham CC, Bailey SM: Ethanol consumption and liver mitochondria function. Biol Signals Recept 2001;10:271–282. 10 Salo JA: Ethanol-induced mucosal injury in rabbit oesophagus. Scand J Gastroenterol 1983;18:713–721. 11 Cohen SM, Ellwein LB: Cell proliferation in carcinogenesis. Science 1990;249:1007–1011. 12 Seitz HK, Poschl G, Simanoski UA: Alcohol and cancer. Recent Dev Alcohol 1998;14:67– 95. 13 Wight AJ, Ogden GR: Possible mechanisms by which alcohol may inﬂuence the development of oral cancer – a review. Oral Oncol 1998;34: 441–447. 14 Salaspuro M: Microbial metabolism of ethanol and acetaldehyde and clinical consequences. Addiction Biol 1997;2:35–36. 15 Salaspuro M: Acetaldehyde, microbes, and cancer of the digestive tract. Crit Rev Clin Lab Sci 2003;40:183–208. 16 Homann N, Jousimies-Somer H, Jokelainen K, Heine R, Salaspuro M: High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenic implications. Carcinogenesis 1997;18:1739–1743.

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17 IARC: Acetaldehyde. IARC Monographs on the Evaluation of the Carcinogenic Risk to Humans. Re-Evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide. Lyon, International Agency for Research on Cancer, 1999, vol 71, pp 319–335. 18 Fang JL, Vaca CE: Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis 1997; 18: 627–632. 19 Helander A, Lindahl-Kiessling K: Increased frequency of acetaldehyde-induced sister chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutat Res 1991;264:103–107. 20 Obe G, Jonas R, Schmidt S: Metabolism of ethanol in vitro produces a compound which induces sister chromatid exchanges in human peripheral lymphocytes in vivo: acetaldehyde not ethanol is mutagenic. Mutat Res 1986;174: 47–51. 21 Mason JB, Choi SW: Effects of alcohol on folate metabolism: implications for carcinogenesis. Alcohol 2005;35:235–241. 22 Shaw S, Jayatilleke E, Herbert V, Colman N: Cleavage of folates during ethanol metabolism. Biochem J 1989;257:277–280. 23 Sharp L, Little J: Polymorphisms in genes involved in folate metabolism and colorectal neoplasia: a HuGE review. Am J Epidemiol 2004;159:423–443. 24 Homann N, Karkkainen P, Koivisto, Nosova T, Jokelainen K, Salaspuro M: Effects of acetaldehyde on cell regeneration and differentiation of the upper gastrointestinal tract mucosa. J Natl Cancer Inst 1997;89:1692–1697. 25 Woutersen RA, Appelmann LM, van Garderen-Hoetmer A, Feron VJ: Inhalation toxicity of acetaldehyde in rats. III. Carcinogenicity study. Toxicology 1986;41:213–231. 26 Rolla R, Vay D, Mottaran E, Parodi M, Traverso N, Arico S, Sartori M, Bellomo G, Klassen LW, Thiele GM, Tuma DJ, Albano E: Detection of circulating antibodies against malondialdehyde-acetaldehyde adducts in patients with alcohol-induced liver disease. Hepatology 2000;31:878–884. 27 Latvala J, Parkkila S, Melkko J, Niemela O: Acetaldehyde adducts in blood and bone marrow of patients with ethanol-induced erythrocyte abnormalities. Mol Med 2001; 7: 401– 405.

28 Viitala K, Makkonen K, Israel Y, Lehtimaki T, Jaakkola O, Koivula T, Blake JE, Niemela O: Autoimmune responses against oxidant stress and acetaldehyde-derived epitopes in human alcohol consumers. Alcohol Clin Exp Res 2000;24:1103–1109. 29 Yokoyama A, Kato H, Yokoyama T, Tsujinaka T, Muto M, Omori T, Haneda T, Kumagai Y, Igaki H, Yokoyama M, Watanabe H, Fukuda H, Yoshimizu H: Genetic polymorphisms of alcohol and aldehyde dehydrogenases and glutathione S-transferase M1 and drinking, smoking, and diet in Japanese men with esophageal squamous cell carcinoma. Carcinogenesis 2002;23:1851–1859. 30 Tuma DJ, Casey CA: Dangerous byproducts of alcohol breakdown – focus on adducts. Alcohol Res Health 2003;27:285–290. 31 Clemens DL, Forman A, Jerrells TR, Sorrell MF, Tuma DJ: Relationship between acetaldehyde levels and cell survival in ethanol-metabolizing hepatoma cells. Hepatology 2002; 35: 1196–1204. 32 Niemela O: Aldehyde-protein adducts in the liver as a result of ethanol-induced oxidative stress. Front Biosci 1999;4:d506–d513. 33 Niemela O: Distribution of ethanol-induced protein adducts in vivo: relationship to tissue injury. Free Radic Biol Med 2001; 31: 1533– 1538. 34 Tuma DJ, Sorrell MF: The role of acetaldehyde adducts in liver injury; in Hall P (ed): Alcoholic Liver Disease: Pathology and Pathogenesis. London, Arnold, 1995, pp 89–99. 35 Rigamonti C, Mottaran E, Reale E, Rolla R, Cipriani V, Capelli F, Boldorini R, Vidali M, Sartori M, Albano E: Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology 2003;38: 42–49. 36 Cunningham CC, Van Horn CG: Energy Availability and alcohol-related pathology. Alcohol Res Health 2003;27:291–299. 37 Pai JK, Hankinson SE, Thadhani R, Rifai N, Pischon T, Rimm EB: Moderate alcohol consumption and lower levels of inﬂammatory markers in US men and women. Atherosclerosis 2005, in press. 38 Rehm J, Gutjahr E, Gmel G: Alcohol and allcause mortality: a pooled analysis. Contemp Drug Probl 2001;28:337–361. 39 Rehm J, Room R, Graham K, Monteiro M, Gmel G, Sempos CT: The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease – an overview. Addiction 2003;98:1209–1228.

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Here, we critically review the most important methods and results of animal models concerning acute and chronic alcoholic damage of the organs belonging to the digestive tract. Acute ethanol administration will be deﬁned as either single doses or exposure to ethanol for up to 24 h. Chronic ethanol administration will be deﬁned as the application or ad libitum consumption of ethanol for at least 5 days in a row with no upper limit. In table 1, we describe the most common techniques and discuss the advantages and disadvantages of the animal models used in gastrointestinal alcohol research.

Animal Models of Ethanol Effects on the Esophagus

Several models have been applied to test the acute and chronic effect of ethanol on the animal esophagus, since the impact of ethanol consumption on the genesis of esophageal diseases in humans has not been completely elucidated (e.g. motoric dysfunction, gastroesophageal reﬂux disease or esophageal cancer). Acute Effects on the Esophagus The model of esophageal intubation (‘gavage’; table 1) is the most effective and most widely used tool to study the acute topic effect of ethanol on the esophageal epithe-

Table 1. Most commonly used animal models in gastrointestinal alcohol research: methods, advantages, disadvantages Model explanation

Organs

Main ﬁelds/questions of application

Alcohol solution and/or water ad libitum

Animals have free access to ethanol solution and/or water

Esophagus, stomach, small intestine

Acute effect on morphological changes, motility disorders; functional changes in organ physiology during chronic consumption

Esophageal/gastric intubation (‘gavage’)

Ethanol is administered via temporary cannulation of esophagus or stomach

Esophagus, small intestine, large intestine, pancreas, liver

Acute effect on morphological changes, motility disorders

Liquid diet, calorie-adjusted (Lieber-DeCarli diet, no water ad libitum)

All nutrients provided in liquid diet; ethanol counts 36% of calorie content; littermates receive carbohydrates as substitute

Small intestine, large intestine, pancreas, liver

Acute effect on morphological changes; chronic effect on carcinogenesis

Intragastric via gastrostomy (Tsukamoto-French model)

Ethanol administration via permanent gastric cannulation (implanted surgically)

Pancreas, liver

Chronic effect on liver pathology, metabolism, signal transduction, ﬁbrogenesis; development of alcoholic pancreatitis

Intraperitoneal/intravenous injection

Direct application of ethanol into circulation via syringe

Esophagus, large intestine

Acute effect on metabolic changes, bacterial acetaldehyde production; chronic effect on carcinogenesis

Cell culture (primary cells, recombinant cells, immortalized cells, mono-/co-culture)

Analysis of either freshly isolated cells from chronically ethanol-fed animals or acute ethanol administration into culture media

Stomach (parietal cells), pancreas (acinus cells), liver (hepatocytes, Kupffer cells, stellate cells)

Studies on effects on cellular signal transduction, metabolism, toxicity, cell death, cell protection mechanisms

Isolated organs (e.g. perfused, in situ)

Organs removed from animal and perfused with media containing ethanol or left in situ but uncoupled from blood circulation

Stomach, small intestine, pancreas, liver

Studies on acute and chronic effects on metabolism, morphology, organ function

Speciﬁcally manipulated breeding by removing or replacing genes in embryonic cells

Liver

Formation/prevention of steatosis, ﬁbrosis, cirrhosis; metabolic changes, hepatocyte apoptosis/necrosis in acute and chronic application

In vivo models

In vitro models

Genetic models Knockout animals/transgenic animals

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lia and to analyze the mechanisms of ethanol-related carcinogenesis, because it offers the possibility of exact control over the amount of ethanol applied (e.g. to analyze dose-response effects). According to ﬁndings in the intubation model, ethanol concentrations of 1 and 5% (v/v) caused dose-dependent alterations in ion transport and tissue barrier function but without histological changes in rabbit esophageal mucosa. Concentrations of 110% lead to increasing mucosal edema [4, 5]. Ethanol concentrations of 120% severely injured the esophageal mucosa, which could be potentiated by HCl [4–6]. In the intubation model, acute ethanol administration had a dose-dependent, co-carcinogenic potency in the rat

esophagus in combination with nitrosamines. The nonalcoholic components of different alcoholic beverages may amplify this co-carcinogenic effect of ethanol. Calvados and red wine appeared to have the highest co-malignant potency [7]. Ethanol-induced motoric dysfunction of the esophagus, often seen in human alcoholics, was conﬁrmed in a cat model of intravenous ethanol infusion [8] and ethanol administration on isolated organs [9] (table 1). Bloodborne ethanol produced a signiﬁcant but dose-independent decrease in lower esophageal sphincter pressure and amplitude [8]. However, these ethanol actions were reversible, not cytotoxic and partially mediated by cholinergic stimulation [9].

Preferred animal species

Major advantages

Major disadvantages

References

Rats, mice

Physiological approach; mostly resembling human behavior

No exact control over ethanol intake possible; only low amounts of ethanol intake

10–12, 31, 43, 67

Rats, mice, rabbits

Exact control over administered ethanol dose; mostly suitable for acute administration

Not suitable for chronic (permanent) ethanol administration; stressful and unphysiological

4–7, 89–91

Rats, mice, primates (baboons)

No bias by non-alcoholic nutrients due to exactly similar caloric intake for littermate controls

Considerable differences between animal and human pathology (e.g. liver damage)

30, 94

Possibility of high blood alcohol levels; total control of ethanol intake; animal pathology resembling human condition

Surgical expertise necessary; expensive maintenance; not suitable for acute studies; unphysiological

Rats, mice

Exact control over administered ethanol dose; avoidance of ﬁrst-pass metabolism; mostly suitable for acute administration

Not suitable for chronic (permanent) ethanol administration; unphysiological; no studies of topical ethanol effect possible

48, 49

Rats, mice

Only possibility to study molecular mechanisms of ethanol; studies on subcellular level (e.g. organelles)

Lack of inﬂuence from other organ systems; problematic extrapolation to in vivo condition

101, 105

Rabbits, rats, dogs

Isolated focus on organ of interest; exclusion of bias by other organs/cells/metabolites/ﬁrst-pass metabolism

Unphysiological; difﬁcult to transfer to the human condition

9, 36–39, 89

Mice (exclusively)

Speciﬁc and systematic analysis of gene or gene product and its relation to acute or chronic ethanol administration

Unphysiological; problematic transfer to the human condition; methodologically difﬁcult

107–111

Rats, mice

Animal Models and Their Results in Gastrointestinal Alcohol Research

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73, 95, 96, 107

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Chronic Effects on the Esophagus Most studies of chronic ethanol exposure on the esophagus applied ad libitum models of ethanol consumption mainly due to the minimization of technical effort, but to the expense of the accuracy of the amount of ethanol applied (table 1). Chronic consumption of ethanol signiﬁcantly enhanced the mitosis rate of esophageal epithelial cells in comparison to non-alcoholic controls as a sign of pre-malignant cell proliferation [10] and acted as a powerful co-carcinogen in combination with different components of cigarette smoke, e.g. nitrosamines, in rodents [11]. In contrast to acute ethanol effects, male cats accustomed to long-term ethanol consumption had signiﬁcantly higher pressure and contraction amplitudes of the lower esophagus especially in withdrawal phases but not for the period of chronic intoxication [12]. Despite the great research efforts in animals, models of chronic ethanolrelated esophageal dysfunction have not yet been able to sufﬁciently elucidate the mechanisms of the human disease.

Animal Models of Ethanol Effects on the Stomach

Acute consumption of pure ethanol as well as alcoholic beverages is associated with acute gastric mucosal hemorrhage in humans [13]. However, chronic ethanol does not seem to be related to the development of gastric cancer in human beings [14–16]. Acute Effects on the Stomach The most common method used to evaluate the acute effect of ethanol on the gastric epithelium was the topical, i.e. intragastric application of ethanol by intubation/gavage. Oral ad libitum models were also utilized, although the amount of ethanol causing the acute effects is very difﬁcult to control in these models (table 1). In humans, ethanol inhibits gastric emptying in comparison to water or glucose control solutions. In a rat model of gastric ethanol administration via gavage, inhibitory capsaicin-sensitive neurons of the vagal nerve as well as type-A cholecystokinin (CCK) receptors were discovered to be responsible for ethanol-induced inhibition of gastric motility [17, 18]. The threshold for ethanol-derived mucosal damage in canine gastric epithelium ranged between concentrations of 8 and 14% (v/v) [19, 20]. Gastric mucosal injury is thought to occur due to the weakening of mucosal barrier

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function, the main protection of the gastric mucosa against gastric acid. Ethanol concentrations of 114% (v/v) lead to an increase in epithelial permeability as a consequence of changes in cellular potential difference caused by re-diffusion of H+ ions through the injured mucosa [19, 20]. Furthermore, ethanol acts as an acute pro-inﬂammatory agent. Concentrations of !10% (v/v) caused a dosedependent adherence of neutrophils with subsequent cellular damage to the gastric epithelium in rats. Higher concentrations resulted in neutrophil-independent damage of the gastric mucosa [21], mainly due to early vascular damage and decreased gastric mucosal blood ﬂow [22]. Thus, very high ethanol concentrations (90–100% v/v) have frequently been used as an effective agent to achieve gastric lesions in animals. Further examinations in rats exposed to acute intragastric ethanol plus tobacco smoke revealed a synergistic deleterious effect on the gastric mucosa due to decreased mucosal blood ﬂow, aggravation of inﬂammation and an increase in free radical production [23, 24]. Concerning the acute action of ethanol on gastric acid secretion, various animal models including dogs, rats or guinea pigs were studied extensively in earlier examinations with inconsistent results [25, 26]. Interestingly, in the rat, Teyssen et al. [27] showed that the non-alcoholic components of brewed alcoholic beverages, produced during the process of fermentation of carbohydrates, are the main stimulating agents of gastric acid secretion. These agents proved to be maleic and succinic acid which are removed in hard liquors during the process of distillation [28]. In a model of Helicobacter pylori-infected Mongolian gerbils (a small rodent species), an aggravating effect of oral ethanol administration (40%) on mucosal inﬂammation could be observed prior to H. pylori infection of the stomach [29]. Chronic Effects on the Stomach The most frequently used models in studies of the chronic effects on the stomach are the ad libitum consumption or administration of the Lieber-DeCarli diet (36% of the daily caloric intake consisting of ethanol) [30] (table 1). Chronic ad libitum consumption led to signiﬁcant hypertrophy of the gastric mucosa as a reaction to the irritant substance ethanol [31, 32], but the development of cancer could not be detected. This hypertrophy is thought to be due to an overexpression of epidermal growth factor and transforming growth factor (TGF)- as a reaction to

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the enhanced occurrence of free oxygen radicals and lipid peroxidation [33]. It is also directly correlated with lipid peroxidation [34]. However, this gastric epithelial hypertrophy observed in rat models seems to be irrelevant for human conditions, since chronic alcohol consumption in humans does not seem to be a risk factor for gastric cancer [14–16]. Furthermore, high ethanol concentrations (96% v/v) caused progressive damage to the gastric intramural neurons with damage to the intracellular mitochondria possibly contributing to ethanol-induced inhibition of gastric motility [35]. Generally, there is still an enormous need for studies in animal models deﬁning the molecular mechanisms of the effects of ethanol or the non-alcoholic ingredients of alcoholic beverages on the stomach.

Chronic Effects on the Small Intestine Similar to the effects of acute ethanol administration, chronic ad libitum ethanol feeding (32% v/v) of rats resulted in ultrastructural derangements (e.g. swollen mitochondria with ruptured cristae, dilated smooth endoplasmatic reticulum). Interestingly, alterations were more evident in the distal ileum than in the proximal jejunum implying that these ﬁndings must be attributed to bloodborne ethanol [43]. Ethanol doses of 15% (v/v) led to decreased crypt cell proliferation, whereas low concentrations (1%) induced an enhancement of crypt cell regeneration in rats [44]. Chronic feeding of a Lieber-DeCarli diet increased the permeability of the small bowel for macromolecules as seen after acute ethanol administration [45]. In contrast to ﬁndings in the duodenum and stomach, chronic ethanol feeding (3% v/v for 8 weeks) did not affect the motility of the ileum in rats [46].

Animal Models of Effects on the Small Intestine

Most of the recent concepts concerning the pathophysiological sequelae of ethanol effects on gut morphology and function in humans are based on ﬁndings in animal models. Acute Effects on the Small Intestine In rabbit models of the ethanol-perfused jejunum (table 1), acute ethanol dose dependently led to microvascular stasis, increased transcapillary ﬂuid and protein loss, epithelial edema causing blebs at the tips of the villi, villus shrinking and rupture of intraepithelial junctions [36– 39]. The main cause of jejunal ethanol-derived damage was oxidative stress induced by leukocytes [38]. An increase in epithelial permeability lead to a dose-dependent increased uptake of macromolecules including endotoxin [37, 40], causing, e.g., ethanol-related liver disease. Besides its effect on epithelial morphology, acute ethanol administration inﬂuenced several aspects of gut function such as uptake of nutritive substances, water and electrolytes and might therefore contribute to malnutrition, which is frequently observed in chronic alcoholism [25, 26]. Acute ethanol may also impair intestinal motility. In a model of intraperitoneal ethanol administration in rats, the production of contractile proteins in the jejunum and ileum was signiﬁcantly lower when compared to salinetreated controls [41, 42]. This aspect may also contribute to acute intestinal disorders (e.g. diarrhea) frequently seen after binge drinking in humans.

Animal Models and Their Results in Gastrointestinal Alcohol Research

Animal Models of Ethanol Effects on the Colon and Rectum

Ethanol consumption is associated with an increased risk of rectal cancer in humans. Interestingly, the main amount of ethanol in the colon and rectum after ethanol consumption results from blood alcohol diffusing into the lumen of the large bowel, because orally consumed ethanol is almost completely absorbed in the upper small intestine [47]. The concentration of ethanol in the large bowel equals the blood concentration after the distribution phase [47]. Acute Effects on the Colon and Rectum Due to the lack of intestine-derived ethanol, models of the intraperitoneal administration of ethanol were especially utilized in this ﬁeld of interest (table 1). Acute intraperitoneal ethanol injection in rats (2.5 g/kg body weight) led to an enhanced crypt cell regeneration in the colon correlating with the intracolonic concentration of acetaldehyde [48]. The ﬁrst and most toxic ethanol metabolite, acetaldehyde, is suspected to promote colonic/ rectal carcinogenesis after long-term alcohol consumption in humans and animals by forming mixed acetals with exocyclic amino groups of ribonucleosides and deoxyribonucleosides. Earlier studies examining acute intraperitoneal ethanol administration revealed a signiﬁcantly higher concentration of acetaldehyde in the rectum, clearly correlating with the number of fecal bacteria. Additionally, germ-free rats showed signiﬁcantly lower

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values of intramucosal acetaldehyde in the colon as well as in the rectum after acute ethanol exposition implying that alcohol dehydrogenase of fecal bacteria plays a dominant role in colonic and rectal acetaldehyde production [49]. Another mechanism of ethanol-derived carcinogenesis was attributed to impaired retinoid signal transduction. Parlesak et al. [50] found decreased colonic cytosolic retinol oxidation and retinoic acid formation in the mucosal cells of rats incubated with ethanol. Chronic Effects on the Colon and Rectum Experiments in animal models of long-term ethanol administration have demonstrated that alcohol per se is not carcinogenic but rather exerts tumor-promoting and co-carcinogenic properties via acetaldehyde, which covalently binds to RNA and DNA [49]. Most examinations of the effect of chronic alcohol administration were performed using a Lieber-DeCarli liquid diet in rats. In this rat model, chronic ethanol administration resulted in enhanced proliferation of rectal mucosal cells as well as earlier and higher tumor formation when combined with carcinogens [49, 51–53]. The main acetaldehyde-producing enzyme is alcohol dehydrogenase, which can be found in mucosal cells of the large intestine as well as in fecal bacteria [49]. In addition, the so-called microsomal ethanol-oxidizing system (MEOS) contributes to acetaldehyde production. Hakkak et al. [54] proved that the MEOS (namely cytochromes P450 2E1 and P450 2C7) was inducible by chronic ethanol feeding in the colonic mucosa, thus contributing to increased intracolonic production of acetaldehyde. As a further mechanism of ethanol-related carcinogenesis, Choi et al. [55] observed genomic DNA hypomethylation in the colonic mucosa due to inhibition of folic acid in rats after feeding a Lieber-DeCarli diet for 4 weeks. Regarding the impact of the non-alcoholic components of beer on colonic and rectal tumorigenesis, the equivalent amount of ethanol and beer did not differ in the cancer development rate when administered simultaneously with the carcinogen azoxymethane [56].

Animal Models in Alcoholic Pancreatitis

The majority of patients with chronic pancreatitis present a history of excessive alcohol consumption, but the underlying pathophysiological mechanisms remain unidentiﬁed [57]. Little is known about the earliest effects of alcohol on the pancreas, and why only a minority of

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alcoholics ever develop clinical pancreatitis [58]. Several animal models have been used to investigate the effects of acute and chronic alcohol application on the development of pancreatitis [59]. Acute Ethanol Administration Despite considerable effort, no animal model has been developed in which acute experimental pancreatitis is induced by acute ethanol application alone [60, 61]. Thus, acute ethanol administration has been combined with other factors that lead to pancreatic damage or that render the animal more susceptible to develop pancreatic injury. The interaction between (i) oral ethanol ingestion, (ii) physiological stimulation of the gland with CCK and secretin, and (iii) short-term obstruction of the pancreatic duct led to acute pancreatitis in rats [61]. Only the combination of all three factors induced pancreatic damage. In another protocol, stimulation of pancreatic secretion with caerulein together with acute ethanol application led to acute necrotizing pancreatitis. Caerulein application alone induced only edematous pancreatic injury demonstrating the enhanced vulnerability of the pancreas under ethanol administration [62]. The inﬂuence of ethanol application on pancreatic blood ﬂow has been investigated in several studies. In dogs, the intravenous infusion of ethanol induced a reduction in pancreatic blood ﬂow [63]. In cats, pancreatic damage resembling human chronic pancreatitis was created by partial pancreatic duct ligation. In these animals, basal pancreatic blood ﬂow was already reduced to 51% of normal. After acute ethanol administration, pancreatic blood ﬂow diminished in all animals, however, the magnitude of the reduction was greater in cats with chronic pancreatitis (50 vs. 31%) and the duration of diminished blood ﬂow was prolonged [64]. In ethanol-treated rats, pancreatic hemoglobin oxygen saturation was signiﬁcantly decreased and remained depressed for over 1 h, whereas the pancreatic hemoglobin content remained unaffected. Of note, similar measurements in the stomach and kidney were unremarkable suggesting a possible link between ethanol-induced ischemia and pancreas-speciﬁc organ damage [65]. The acute effects of ethanol on the pancreas were also studied with the infusion of non-oxidative products of ethanol metabolism in rats [66]. After intravenous infusion of fatty acid ethyl esters, an increase in pancreatic edema formation, pancreatic trypsinogen activation and vacuolization of acinar cells was demonstrated suggesting an organspeciﬁc toxic effect of these ethanol metabolites [66].

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Chronic Ethanol Administration Pancreatic alterations have been demonstrated in animal models with prolonged alcohol feeding alone and with prolonged alcohol feeding in combination with other procedures such as pancreatic duct obstruction or chemical induction of preexisting pancreatic damage. Chronic Alcohol Feeding Alone Sarles et al. [67] fed rats with 20% alcohol ad libitum for a period of 20–30 months. Half of the animals developed protein plugs in the pancreatic ducts with sclerosis of the pancreas together with focal loss of acinar area. Pancreatic injury was also demonstrated in dogs equipped with gastric and duodenal cannulae after alcohol administration together with a diet rich in fat and protein for 2–3 years [68]. However, other investigators failed to reproduce these morphological changes in ethanol-fed rats [69]. The ductal plugs observed in ethanol-fed rats have also been reported in control animals [70], and have occurred spontaneously in 15- to 17-month-old rats [60]. The reasons for these conﬂicting data are unclear. In studies from the early 1970s, ethanol in water was used as the sole source of drinking ﬂuid, and the total intake of ethanol was variable and hard to quantify [71]. Another reason may be that prolonged ethanol intake leads to variations in caloric intake with further effects on pancreatic function which are difﬁcult to assess as well [72]. The failure of most animal models of chronic alcohol consumption to develop pancreatitis may result from the ingestion of relatively lower amounts of alcohol than human alcoholics. Thus, feeding protocols such as the Tsukamoto-French model [73] (table 1) have been used in pancreatic research. This model allows independent control over ethanol and nutrient intake with implanted gastrostomy catheters, and allows the administration of higher doses of alcohol. Using this experimental model, rats were fed continuously with ethanol and a liquid diet containing different amounts of fat [74]. Sustained blood ethanol levels were achieved, and after 30–160 days, pancreatic tissue was examined. In animals without ethanol consumption or receiving ethanol together with a low-fat diet, pancreatic histology was either unremarkable or showed only mild pancreatic damage such as steatosis. In rats receiving ethanol together with a high-fat diet, pancreatic damage was observed such as hypogranulation and apoptosis of acinar cells, and focal lesions of chronic pancreatitis such as fat necrosis, mononuclear cell inﬁltration, ﬁbrosis, acinar atrophy, ductal dilatation, and intraductal plugs were present in up to 30% of the animals. It was suggested that

Animal Models and Their Results in Gastrointestinal Alcohol Research

dietary fat potentiates ethanol-induced pancreatic injury [74]. In a similar study, rats were fed with ethanol and either saturated or unsaturated fat [75]. The dose of ethanol was gradually increased as tolerance developed, thereby allowing the administration of a higher dosage of alcohol. After 4 weeks, acinar cell atrophy, fatty inﬁltration of pancreatic acinar and islet cells, inﬁltration of inﬂammatory cells and focal necrosis was observed in rats receiving high-dose ethanol with unsaturated fat. After 8 weeks, focal ﬁbrosis developed in this group, and radical adducts were also signiﬁcantly increased. The effects were blunted by administration of dietary saturated fat. The authors concluded that the total amount of ethanol consumption and the type of dietary fat represent the important factors for pancreatic damage in this experimental model [75]. The possible role of oxidative stress in the development of chronic pancreatitis has also been addressed in studies with ethanol-fed rats. In one study, histological examination of pancreatic tissue revealed only mild acinar steatosis after long-term ethanol administration, but free radical adducts were demonstrated in pancreatic secretions [73]. In another investigation, an elevation in oxidative stress markers was found in pancreatic tissue. Since histological pancreatic damage was not observed, the elevation in oxidative stress markers was suggested to occur as a primary phenomenon rather than as part of an inﬂammatory response [76]. In a recent study with Lieber-DeCarli ethanol-fed rats, pancreatic gene expression was investigated using mRNA differential display [77]. Pancreatic cholesterol esterase mRNA levels were enhanced in the pancreas and liver, and similar patterns were found for other fatty acid ethyl ester-related genes suggesting that the pancreatic cholesterol esterase gene might play an important role in the development of alcohol-related pancreatic damage [77]. The effects of chronic alcohol consumption on pancreatic gene expression and glandular content of pancreatic enzymes were studied in rats [78]. Messenger RNA levels for lipase, trypsinogen, chymotrypsinogen and cathepsin B were elevated in ethanol-fed rats suggesting that chronic ethanol consumption increases the capacity of the pancreatic acinar cell to synthesize digestive and lysosomal enzymes, and that these changes might lead to an elevated susceptibility of the pancreas to enzyme-related damage [78]. However, ethanol-fed rats receive less dietary carbohydrates than their controls under the Lieber-DeCarli feeding protocol. The synthesis and secretion of pancreatic enzymes is highly sensitive to dietary variations [79], and therefore, it has been claimed that the ob-

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served changes in pancreatic enzyme content are a result of the different carbohydrate intakes. In order to clarify this issue, the pancreatic content and mRNA levels for pancreatic digestive enzymes were subsequently measured in rats under feeding patterns with both high- and low-carbohydrate diets with and without ethanol [79]. The previously observed effects of alcohol consumption were independent of the carbohydrate content of the diet, and it was concluded that the changes in pancreatic enzyme activities are due to ethanol itself [79]. However, only initial lesions of chronic alcoholic pancreatitis resembling the human disease have been evoked with alcohol feeding alone. Therefore, alcohol feeding was combined with other procedures to study the effects of ethanol on the pancreas. Chronic Alcohol Feeding in Combination with Other Procedures According to the observations of Sarles et al. [67], obstruction of the small pancreatic ducts is a consistent ﬁnding in initial lesions of human chronic pancreatitis. As a result, the combination of ethanol administration and pancreatic duct obstruction has been studied in different animal models. In dogs, incomplete pancreatic duct obstruction was achieved with surgical intervention [80]. Ethanol-fed animals without pancreatic duct obstruction demonstrated no pancreatic injury, whereas ethanol-fed animals with pancreatic duct obstruction showed reduced exocrine pancreatic function and histological damage with ﬁbrosis, parenchymal cell loss, and chronic inﬂammatory cell inﬁltration [80]. In rats, obstruction of the pancreatic duct was achieved with ethibloc application, a tissue adhesive which is totally decomposed by the organism within 2 months [81]. Application of ethibloc alone resulted in pancreatic injury with extensive ﬁbrosis, inﬂammatory cell inﬁltration, and acinar cell degeneration. However, these injuries were reversible after ethibloc decomposition. Further prolonged alcohol administration with an intragastric cannulae inhibited the recovery, and resulted frequently in parenchymal calciﬁcations. Pancreatic regeneration was less pronounced in ethanol-fed animals, and calciﬁcations remained in some animals [81]. Hyperstimulation of the pancreas with supramaximal doses of CCK increases exocrine pancreatic secretion and induces acute edematous pancreatitis. Rats received an ethanol diet for 2 or 6 weeks according to the TsukamotoFrench model [82]. Then, the animals were infused CCK8 at a dose which by itself previously did not induce pancreatitis. The ethanol-fed animals showed more inﬂammatory cell inﬁltration and more apoptotic cells in the

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pancreas suggesting an increased sensitivity of rats to pancreatitis after prolonged ethanol application [82]. Recently, in rats fed the Lieber-DeCarli alcohol diet, Deng et al. [83] conﬁrmed that ethanol alone cannot induce chronic pancreatitis, but signiﬁcantly increases the susceptibility of the organ toward inﬂammation and accelerates ﬁbrogenesis during the development of chronic alcoholic pancreatitis.

Animal Models of Ethanol Effects on the Liver

Alcoholic liver disease (ALD) is still one of the most frequently seen consequences of long-term ethanol consumption in every day clinical practice. However, the mechanisms leading to ALD are not yet completely understood. Thus, the liver is the most frequently and intensively studied organ in animals concerning the deleterious effects of ethanol consumption. Acute Effects of Ethanol on the Liver Findings in several different animal models have convincingly proved that even a single dose of alcohol exerts acute effects on liver function. To examine acute ethanol effects on the liver, most studies applied gastric intubation or intraperitoneal injection in rodents. Interestingly, the most commonly used amount of ethanol to mimic socalled human binge drinking was 5–6 g/kg body weight, which approximately resembles 0.75 liters of whiskey (40% v/v) in a 75-kg human. Acute ethanol effects on the liver caused alterations in liver morphology such as hepatocyte swelling and a decrease in sinusoidal fenestrae as seen by electron microscopy in pigs and rats [84, 85]. Also, the hepatic microcirculation was acutely impaired. Narrowed vessels and partially occluded sinusoids due to erythrocyte stasis led to decreased liver blood ﬂow, thus disturbing the transport of plasma substances from the sinusoids to hepatocytes and impairing hepatic metabolic capacity [84–87]. Another important aspect of transient functional deterioration and permanent injury of the liver due to acute ethanol administration is the activation of Kupffer cells. Acute ethanol ingestion of 4 g/kg ethanol in mice lead to activation of Kupffer cells as indicated by pseudopodia and ﬁlopodia [86] after an initial ethanol-induced tolerance [88]. Studies in rats using the gastric intubation model for administration of a single ethanol binge showed that activated Kupffer cells are the main source of reactive oxygen species (ROS) like the superoxide anion O2– in early liver injury [89, 90].

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ROS trigger liver injury by a variety of different pathways. In a binge-drinking mouse model Mansouri et al. [91] proved that acute ethanol leads to hepatic DNA depletion mainly in the mitochondria and to lipid peroxidation, both triggering apoptosis and necrosis in hepatocytes. These ﬁndings were conﬁrmed by Navasumrit et al. [92]. After a single dose of ethanol (5 g/kg) single-strand breaks in DNA increased from 1 h to peak at 6 h. Interestingly, the generation of hydroxyethyl radicals was attenuated by the prior intraperitoneal administration of the antioxidant vitamins C and E. These results represent a startling but yet undeﬁned link between carcinogenesis and acute ethanol effects possibly accumulating after frequent recurrence of binge drinking. Furthermore, acute ethanol administration caused mitochondrial lipid hydroperoxide formation in rats in conjunction with a marked impairment in mitochondrial oxidative function due to glutathione depletion, which entailed deterioration of liver protection against oxidative stress [93]. Chronic Effects of Ethanol on the Liver Lieber-DeCarli Diet Lieber et al. [30] were the ﬁrst investigators to convincingly prove the direct toxic effect of ethanol on the liver in an animal model. Rats receiving a liquid diet (in which carbohydrates of up to 36% of total energy had been replaced by ethanol) developed fatty livers with a signiﬁcant rise in triglycerides and hepatic cholesterol esters. Pair-fed controls obtaining 16% of total energy as protein, 43% as fat and 31% as carbohydrate showed no abnormalities. These experiments disproved the prevailing assumption until that decade that ethanol had no pathologic effect on the liver without concomitant malnutrition. However, no inﬂammation, ﬁbrosis or cirrhosis could be demonstrated. In the meantime, rats fed the Lieber-DeCarli diet became a well-accepted model to study the chronic effects of ethanol on liver function. Due to the fact that rats fed the Lieber-DeCarli diet reduce their overall food intake, pair-fed control animals are mandatory to interpret the experimental results. Following the determination of the caloric intake of the ethanol-treated rat, the exact amount of calories is given to the pair-fed control animal on the next day. A major breakthrough was achieved in 1974 by Lieber and DeCarli [94] who fed baboons an adapted LieberDeCarli diet, in which fat accounted for 21%, protein for 18% and carbohydrate for 61% of the total caloric intake

Animal Models and Their Results in Gastrointestinal Alcohol Research

in the pair-fed control group. In the alcohol-containing diet, ethanol replaced carbohydrate isocalorically to up to 50% of the total energy – the equivalent of alcohol intake in human alcoholics. All ethanol-treated baboons were histologically proven to have fatty livers after 6 and 12 months. Surprisingly, 30% of the baboons developed cirrhosis after a time period of 5 years. Histologically perivenular ﬁbrosis was demonstrated whereas no signs of inﬂammation were detected. The application of a non-human primate animal model is self-evident, but the long duration and the low outcome of major histological liver changes including cirrhosis represent a major disadvantage to this model. Furthermore, these results could not yet be reproduced by other investigators. Tsukamoto-French Model In 1984, Tsukamoto et al. [95, 96] presented a new animal model of chronic ALD generating severe inﬂammation and necrosis for the ﬁrst time. After laparotomy a catheter was implanted intragastrically facilitating a continuous infusion of ethanol of up to 16.5 g/kg/day. Very high blood-alcohol levels can be achieved through this method, resulting in pathologic changes which resemble human ALD including fatty liver, apoptosis, central necrosis, portal and bridging ﬁbrosis and mixed inﬁltrating inﬂammatory leukocytes [97]. However, a high-iron or high-fat diet containing unsaturated fatty acids is further required to generate the severe signs of liver injury. One drawback of this model is the required surgical skills. Another one is the unphysiological continuous ethanol infusion which completely differs from human drinking behavior. On the other hand, the absolute control of the nutritional intake is a clear advantage of this model. Kupffer Cells, Endotoxin, Cytokines and Mechanisms of Cell Death in Chronic Ethanol Models The purpose of Kupffer cells as an important part of the mononuclear phagocyte system is to clean the portal blood from antigens like endotoxin. Unfortunately, Kupffer cells are also the pivot of chronic alcoholic liver injury. Several studies demonstrated that chronic ethanol intake sensitizes Kupffer cells towards endotoxin (i.e. lipopolysaccharide), which is derived from intestinal gramnegative bacteria due to the increased ethanol-induced gut permeability [40, 45], resulting in the synthesis and secretion of pro-inﬂammatory cytokines and chemokines and the production of ROS [88, 98].

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Especially tumor necrosis factor (TNF)- secreted by ethanol-activated Kupffer cells holds a main function in ALD. Rats receiving 12 g/kg/day of ethanol intragastrically for 4 weeks were injected anti-TNF- antibodies. This signiﬁcantly attenuated hepatic inﬂammation and necrosis [99]. TNF- is mainly produced by activated Kupffer cells via upregulation of the NFB pathway resulting in a subsequent imbalance of pro- and anti-inﬂammatory cytokines, attraction of neutrophils and mononuclear cells and aggravation of liver injury [100]. Furthermore, activated Kupffer cells produce cytokines including TGF-. These cytokines activate hepatic stellate cells, which are mainly responsible for ﬁbrosis in chronic liver disease [97]. Kupffer cells are also involved in gender differences of susceptibility to alcoholic liver injury [88]. In a model of isolated Kupffer cells of male and female rats fed ethanol intragastrically for 4 weeks, Kono et al. [101] showed that females developed steatosis, inﬂammation and necrosis more rapidly compared to male controls. NFB pathway activation and TNF- mRNA expression in hepatocytes from females were threefold higher. The NFB-mediated expression and secretion of TNF- proved to be the critical step accounting for more severe liver injury in females. TNF- may also induce apoptosis in hepatocytes. Conﬂictingly, the NFB pathway usually protects hepatocytes from TNF--induced cell death, but long-term ethanol administration seems to inhibit this protective mechanism, thus sensitizing hepatocytes towards cytokine-dependent apoptosis or necrosis [102]. However, approaches to prevention of Kupffer cell activation in animal models revealed new treatment options of ALD. Gut sterilization with polymyxin B and neomycin prevented liver injury by signiﬁcantly reducing gut-derived endotoxin in rats chronically exposed to alcohol in the Tsukamoto-French model. Consistently, antibiotic treatment prevented not only the elevation in serum transaminases, but reduced the hepatic pathological score [103]. In the same model, depletion of Kupffer cells with gadolinium chloride considerably attenuated the development of fatty liver, inﬂammation and necrosis [104]. Interestingly, deactivation of Kupffer cells prevented liver injury despite the persisting ethanol-mediated induction of cytochrome P450 2E1 (CYP2E1), leading to the assumption that Kupffer cells rather than CYP2E1 play the major role in the initiation of hepatocyte damage caused by alcohol [105]. Moreover, animal models of chronic ethanol administration deﬁned the ambiguous function of acetaldehyde produced by alcohol dehydro-

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genase, CYP2E1 and the ethanol-induced MEOS in ALD. On the one hand, it protects the liver from NFB-induced activation of Kupffer cells [97], and on the other hand, it is responsible for formation of protein-aldehyde adducts causing cell damage [106]. Further Progress by Knockout and Transgenic Mouse Models The recent development of transgenic animals that overexpress particular genes, or of knockout animals in which particular genes have been eliminated, has provided extraordinary possibilities to analyze the effects of ethanol in animals and to test new treatment options for ethanol-related diseases. Until now, these models of genetically modiﬁed animals (table 1) are only available in mice. Kono et al. [107] were able to establish the Tsukamoto-French model, originally designed for the use in rats, in mice, therefore providing the opportunity for knockout studies of ALD. The application of a knockout mouse model conﬁrmed that free radicals generated by NADPH oxidase in Kupffer cells play a pivotal role in ethanol-induced liver injury. In NADPH oxidase-deﬁcient knockout mice fed intragastrically with ethanol for 4 weeks, neither did liver pathology evolve nor were free radicals detectable by electron spin resonance [108]. In addition, Kono et al. [109] questioned the concept that CYP2E1 induced in hepatocytes by chronic ethanol ingestion is a major factor in alcoholinduced liver injury via the generation of free radicals. Liver pathology was indistinguishable in CYP2E1+/+ and CYP2E1–/– female mice following continuous intragastric ethanol feeding for 4 weeks. However, Morgan et al. [110] obtained contrary results in a transgenic mouse overexpressing human CYP2E1, ﬁnding more pronounced liver injury in these chronically alcohol-fed mutant mice compared to wild-type controls. Consequently, CYP2E1 seems to play a noticeable but not the main role in ALD. Yin et al. [111] supported the current understanding that TNF- plays an important role in alcohol-induced liver injury by comparing TNF-receptor 1 (TNF-R1) and TNF-receptor 2 (TNF-R2) knockout mice exposed to alcohol for 4 weeks by the Tsukamoto-French model. Alcohol induced severe inﬂammation and necrosis in TNF-R2 mice, but not in TNF-R1 knockout mice. Taken together, these exemplary studies demonstrate the signiﬁcance of knockout mouse models in alcohol research.

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Conclusions and Future Research

Animal models are an invaluable tool in gastrointestinal alcohol research. The ﬁndings in animal models reveal that ethanol consumption dose-dependently generates epithelial damage in the upper gastrointestinal tract, thus contributing to esophageal dysfunction and gastroesophageal reﬂux disease, and that ethanol acutely and dosedependently increases gut permeability for endotoxin triggering liver damage. Increased gastric acid output is due to maleic and succinic acid present in brewed but not distilled alcoholic beverages. However, many of the molecular mechanisms of the effects of ethanol especially on the upper digestive tract have not yet been elucidated. Chronic ethanol administration causes epithelial hypertrophy and enhanced cell proliferation in the upper and lower digestive tract in animals. Ethanol expedites carcinogenesis of the esophagus and large intestine mainly through its ﬁrst metabolite acetaldehyde binding covalently to DNA, which is mainly derived from intestinal bacteria metabolizing ethanol. Additional noxes, e.g. nitrosamines, may potentiate these co-carcinogenic effects. In the pancreas, no satisfactory animal model has yet been established to investigate all the different pathophysiological mechanisms leading to alcohol-induced pancreatic dysfunction. However, studies in the existing experimental animal models showed that acute ethanol administration selectively reduces pancreatic blood ﬂow and microcirculation thereby suggesting that alcohol may worsen ischemic injury during the development of acute pancreatitis with or without underlying chronic disease. Furthermore, alcohol acutely damages the pancreas through the effects of toxic ethanol metabolites and possibly by limiting pancreatic regeneration. Chronic ethanol administration most probably facilitates the intra-pancreatic activation of digestive enzymes. Although this alone does not cause pancreatitis in the experimental setting, it renders the pancreas more susceptible to enzyme-related injury. Furthermore, nutritional factors might contribute to the development of pancreatitis. The development of pancreatic duct plugs within the course of alcoholic chronic pancreatitis contributes to the progression of the disease. However, since long-term ethanol feeding does not result in typical chronic pancreatitis seen in humans, alcohol may represent a co-factor in the development of chronic pancreatitis in humans with other, yet to be identiﬁed, genetic or environmental factors.

Animal Models and Their Results in Gastrointestinal Alcohol Research

On the other hand, animal models were more successful in reproducing the main features of human ALD, helping to uncover many of the mechanisms involved. Studies in animals demonstrated that gut-derived, mainly gramnegative bacterial components play a pivotal role of in Kupffer cell activation even after a single ethanol binge thus priming the liver for further damage due to ROS, TNF- and mononuclear cell inﬁltration. Furthermore, acute ethanol administration leads to impairment of hepatic microcirculation, deterioration of its metabolic capacity and to apoptotic cell death. Especially the Tsukamoto-French model proved to be a useful tool to study the molecular mechanisms in chronic alcoholic diseases of the liver. Most recently it was also established in knockout mouse strains. In chronic ALD, endotoxin-activated Kupffer cells hold the key function by releasing mainly pro-inﬂammatory or pro-ﬁbrogenic cytokines like TNF- or TGF-, the former triggering ROS production followed by apoptosis and necrosis of hepatocytes, the latter activating hepatic stellate cells leading to ﬁbrosis. Promising efforts in terms of ALD prevention were shown by decreasing the intestinal bacterial ﬂora or blockade of Kupffer cell activation. Studies in knockout models have proved that CYP2E1 seems to play a recognizable but not main role in ALD, whereas animals lacking receptors for TNF- or NADPH oxidase in Kupffer cells show signiﬁcantly less liver injury than wild-type controls after chronic ethanol administration. Still it remains to be elucidated how genetic predisposition causes or even prevents the development of ethanol-related diseases. Furthermore, an immense number of open questions remain regarding the molecular mechanisms of ethanol-derived damage, and they have to be answered using animal models. Most animal studies have been performed using pure ethanol. Since the non-alcoholic components of alcoholic beverages might affect the gastrointestinal organs themselves or possibly potentiate the toxicity of ethanol, commonly ingested alcoholic beverages such as beer, wine, cognac, vodka, and whisky and their non-alcoholic constituents must also be tested in future animal studies.

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Animal Models and Their Results in Gastrointestinal Alcohol Research

58 Haber P, Wilson J, Apte M, Korsten M, Pirola R: Individual susceptibility to alcoholic pancreatitis: still an enigma. J Lab Clin Med 1995; 125:305–312. 59 Schneider A, Whitcomb DC, Singer MV: Animal models in alcoholic pancreatitis – what can we learn? Pancreatology 2002;2:189–203. 60 Sarles H: Chronic calcifying pancreatitis – chronic alcoholic pancreatitis. Gastroenterology 1974;66:604–616. 61 Siech M, Heinrich P, Letko G: Development of acute pancreatitis in rats after single ethanol administration and induction of a pancreatic juice edema. Int J Pancreatol 1991; 8: 169– 175. 62 Foitzik T, Lewandrowski KB, Fernandez-del Castillo C, Rattner DW, Klar E, Warshaw AL: Exocrine hyperstimulation but not pancreatic duct obstruction increases the susceptibility to alcohol-related pancreatic injury. Arch Surg 1994;129:1081–1085. 63 Friedman HS, Lowery R, Shaughnessy E, Scorza J: The effects of ethanol on pancreatic blood ﬂow in awake and anesthetized dogs. Proc Soc Exp Biol Med 1983;174:377–382. 64 Widdison AL, Alvarez C, Schwarz M, Reber HA: The inﬂuence of ethanol on pancreatic blood ﬂow in cats with chronic pancreatitis. Surgery 1992; 112: 202–208; discussion 208– 210. 65 Foitzik T, Fernandez-del Castillo C, Rattner DW, Klar E, Warshaw AL: Alcohol selectively impairs oxygenation of the pancreas. Arch Surg 1995;130:357–361. 66 Werner J, Laposata M, Fernandez-del Castillo C, Saghir M, Iozzo RV, Lewandrowski KB, Warshaw AL: Pancreatic injury in rats induced by fatty acid ethyl ester, a nonoxidative metabolite of alcohol. Gastroenterology 1997; 113:286–294. 67 Sarles H, Lebreuil G, Tasso F, Figarella C, Clemente F, Devaux MA, Fagonde B, Payan H: A comparison of alcoholic pancreatitis in rat and man. Gut 1971;12:377–388. 68 Sahel J, Sarles H, Lebreuil G, Tiscornia O: Alcoholic experimental pancreatitis in dog. Biol Gastroenterol 1975;8:363. 69 Darle N, Ekholm R, Edlund Y: Ultrastructure of the rat exocrine pancreas after long term intake of ethanol. Gastroenterology 1970;58:62– 72. 70 Papp M, Fodor I, Varga G: Development of intraductal protein plugs in rats fed with ethanol for 18 months. Acta Morphol Hung 1984; 32:31–35. 71 Singh M, LaSure MM, Bockman DE: Pancreatic acinar cell function and morphology in rats chronically fed an ethanol diet. Gastroenterology 1982;82:425–434. 72 Chariot J, Roze C, de La Tour J, Souchard M, Hollande E, Vaille C, Debray C: Effects of chronic ethanol consumption on pancreatic response to central vagal stimulation by 2-deoxyD-glucose in the rat. Digestion 1977; 15: 425– 437.

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73 Tsukamoto H, Towner SJ, Yu GS, French SW: Potentiation of ethanol-induced pancreatic injury by dietary fat. Induction of chronic pancreatitis by alcohol in rats. Am J Pathol 1988; 131:246–257. 74 Iimuro Y, Bradford BU, Gao W, Kadiiska M, Mason RP, Stefanovic B, Brenner DA, Thurman RG: Detection of alpha-hydroxyethyl free radical adducts in the pancreas after chronic exposure to alcohol in the rat. Mol Pharmacol 1996;50:656–661. 75 Norton ID, Apte MV, Lux O, Haber PS, Pirola RC, Wilson JS: Chronic ethanol administration causes oxidative stress in the rat pancreas. J Lab Clin Med 1998;131:442–446. 76 Kono H, Nakagami M, Rusyn I, Connor HD, Stefanovic B, Brenner DA, Mason RP, Arteel GE, Thurman RG: Development of an animal model of chronic alcohol-induced pancreatitis in the rat. Am J Physiol Gastrointest Liver Physiol 2001;280:G1178–G1186. 77 Pfützer RH, Tadic SD, Li HS, Thompson BS, Zhang JY, Ford ME, Eagon PK, Whitcomb DC: Pancreatic cholesterol esterase, ES-10, and fatty acid ethyl ester synthase III gene expression are increased in the pancreas and liver but not in the brain or heart with long-term ethanol feeding in rats. Pancreas 2002;25:101– 106. 78 Apte MV, Wilson JS, Korsten MA, McCaughan GW, Haber PS, Pirola RC: Effects of ethanol and protein deﬁciency on pancreatic digestive and lysosomal enzymes. Gut 1995; 36: 287– 293. 79 Apte M, Norton I, Haber P, Applegate T, Korsten M, McCaughan G, Pirola R, Wilson J: The effect of ethanol on pancreatic enzymes – a dietary artefact? Biochim Biophys Acta 1998; 1379:314–324. 80 Tanaka T, Miura Y, Matsugu Y, Ichiba Y, Ito H, Dohi K: Pancreatic duct obstruction is an aggravating factor in the canine model of chronic alcoholic pancreatitis. Gastroenterology 1998;115:1248–1253. 81 Pap A, Boros L: Alcohol-induced chronic pancreatitis in rats after temporary occlusion of biliopancreatic ducts with Ethibloc. Pancreas 1989;4:249–255. 82 Pandol SJ, Periskic S, Gukovsky I, Zaninovic V, Jung Y, Zong Y, Solomon TE, Gukovskaya AS, Tsukamoto H: Ethanol diet increases the sensitivity of rats to pancreatitis induced by cholecystokinin octapeptide. Gastroenterology 1999;117:706–716. 83 Deng X, Wang L, Elm MS, Gabazadeh D, Diorio GJ, Eagon PK, Whitcomb DC: Chronic alcohol consumption accelerates ﬁbrosis in response to cerulein-induced pancreatitis in rats. Am J Pathol 2005;166:93–106. 84 Elmer O, Bengmark S, Goransson G, Sundqvist K, Soderstrom N: Acute portal hypertension after gastric administration of ethanol in the pig. Eur Surg Res 1982;14:298–308.

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85 Takashimizu S, Watanabe N, Nishizaki Y, Kawazoe K, Matsuzaki S: Mechanisms of hepatic microcirculatory disturbances induced by acute ethanol administration in rats, with special reference to alterations of sinusoidal endothelial fenestrae. Alcohol Clin Exp Res 1999;23:39S–46S. 86 Eguchi H, McCuskey PA, McCuskey RS: Kupffer cell activity and hepatic microvascular events after acute ethanol ingestion in mice. Hepatology 1991;13:751–757. 87 Horie Y, Kato S, Ohki E, Tamai H, Yamagishi Y, Ishii H: Hepatic microvascular dysfunction in endotoxemic rats after acute ethanol administration. Alcohol Clin Exp Res 2000;24:691– 698. 88 Thurman RG: II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol 1998;275:G605–G611. 89 Bautista AP, Spitzer JJ: Acute ethanol intoxication stimulates superoxide anion production by in situ perfused rat liver. Hepatology 1992; 15:892–898. 90 Yokoyama H, Fukuda M, Okamura Y, Mizukami T, Ohgo H, Kamegaya Y, Kato S, Ishii H: Superoxide anion release into the hepatic sinusoid after an acute ethanol challenge and its attenuation by Kupffer cell depletion. Alcohol Clin Exp Res 1999;23:71S–75S. 91 Mansouri A, Gaou I, De Kerguenec C, Amsellem S, Haouzi D, Berson A, Moreau A, Feldmann G, Letteron P, Pessayre D, Fromenty B: An alcoholic binge causes massive degradation of hepatic mitochondrial DNA in mice. Gastroenterology 1999;117:181–190. 92 Navasumrit P, Ward TH, Dodd NJ, O’Connor PJ: Ethanol-induced free radicals and hepatic DNA strand breaks are prevented in vivo by antioxidants: effects of acute and chronic ethanol exposure. Carcinogenesis 2000;21:93–99. 93 Trenti T, Sternieri E, Ceccarelli D, Gallesi D, Masini A: Production of lipid hydroperoxides and depletion of reduced glutathione in liver mitochondria after acute ethanol administration to rats. Toxicol Lett 1992; 64–65 Spec No:751–755.

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94 Lieber CS, DeCarli LM: An experimental model of alcohol feeding and liver injury in the baboon. J Med Primatol 1974; 3: 153– 163. 95 Tsukamoto H, Reidelberger RD, French SW, Largman C: Long-term cannulation model for blood sampling and intragastric infusion in the rat. Am J Physiol 1984; 247:R595– R599. 96 Tsukamoto H, French SW, Benson N, Delgado G, Rao GA, Larkin EC, Largman C: Severe and progressive steatosis and focal necrosis in rat liver induced by continuous intragastric infusion of ethanol and low fat diet. Hepatology 1985;5:224–232. 97 French SW: Intragastric ethanol infusion model for cellular and molecular studies of alcoholic liver disease. J Biomed Sci 2001;8: 20–27. 98 Bautista AP: Impact of alcohol on the ability of Kupffer cells to produce chemokines and its role in alcoholic liver disease. J Gastroenterol Hepatol 2000;15:349–356. 99 Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG: Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inﬂammation caused by chronic exposure to ethanol in the rat. Hepatology 1997;26:1530– 1537. 100 Nanji AA, Jokelainen K, Rahemtulla A, Miao L, Fogt F, Matsumoto H, Tahan SR, Su GL: Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology 1999;30: 934–943. 101 Kono H, Wheeler MD, Rusyn I, Lin M, Seabra V, Rivera CA, Bradford BU, Forman DT, Thurman RG: Gender differences in early alcohol-induced liver injury: role of CD14, NFkappaB, and TNF-alpha. Am J Physiol Gastrointest Liver Physiol 2000;278:G652–661. 102 Hoek JB, Pastorino JG: Ethanol, oxidative stress, and cytokine-induced liver cell injury. Alcohol 2002;27:63–68.

103 Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG: Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 1995; 108: 218– 224. 104 Adachi Y, Bradford BU, Gao W, Bojes HK, Thurman RG: Inactivation of Kupffer cells prevents early alcohol-induced liver injury. Hepatology 1994;20:453–460. 105 Koop DR, Klopfenstein B, Iimuro Y, Thurman RG: Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1. Mol Pharmacol 1997;51:944–950. 106 Niemelä O: Aldehyde-protein adducts in the liver as a result of ethanol-induced oxidative stress. Front Biosci 1999;4:D506–D513. 107 Kono H, Bradford BU, Rusyn I, Fujii H, Matsumoto Y, Yin M, Thurman RG: Development of an intragastric enteral model in the mouse: studies of alcohol-induced liver disease using knockout technology. J Hepatobiliary Pancreat Surg 2000;7:395–400. 108 Kono H, Rusyn I, Yin M, Gabele E, Yamashina S, Dikalova A, Kadiiska MB, Connor HD, Mason RP, Segal BH, Bradford BU, Holland SM, Thurman RG: NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. J Clin Invest 2000; 106: 867–872. 109 Kono H, Bradford BU, Yin M, Sulik KK, Koop DR, Peters JM, Gonzalez FJ, McDonald T, Dikalova A, Kadiiska MB, Mason RP, Thurman RG: CYP2E1 is not involved in early alcohol-induced liver injury. Am J Physiol 1999;277:G1259–1267. 110 Morgan K, French SW, Morgan TR: Production of a cytochrome P450 2E1 transgenic mouse and initial evaluation of alcoholic liver damage. Hepatology 2002;36:122–134. 111 Yin M, Wheeler MD, Kono H, Bradford BU, Gallucci RM, Luster MI, Thurman RG: Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 1999;117:942–952.

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gested that the role of alcohol was of much less importance than tobacco or joint alcohol and tobacco exposure. In contrast, some other investigations suggest that alcohol may have a greater inﬂuence on head and neck cancer development [10, 24]. However, the synergistic effect of both seems to give higher risk ratios for head and neck cancer [25]. Additionally, some authors have suggested that alcohol may have an independent effect [23, 26]. For example Tuyns [10] suggested a deﬁnite independent role of alcohol in esophageal cancer, but he could not see this effect in head and neck cancer. In contrast to this result, most other studies and reviews, however, seem to conﬁrm that alcohol does have an independent effect in increasing the risk of head and neck cancer [7, 8, 11, 27, 28]. Herity et al. [29] found an increased risk for oral cancer of 4.6 for light drinkers and ninefold risk for heavy drinkers. Llewelyn and Mitchell [30] recently conﬁrmed once again the association between alcohol and oral cancer, with a site predilection of tongue and ﬂoor of mouth. Jovanovic et al. [31] also found the ﬂoor of mouth to be the high-risk site for alcohol-related oral cancer.

The Dose-Effect Relationship

In a clinical retrospective trial, Maier and Tisch [32] detected a dose-effect relationship between alcohol consumption and the incidence of head and neck carcinomas, with a maximum relative risk for hypopharyngeal carcinoma. Setting the relative risk for an individual with a daily alcohol consumption of 25 g at 1.0, there is an increase in the relative risk for cancer with higher amounts of alcohol, reaching a maximum at 100 g alcohol/day with 32.4 [32]. After establishing the link between head and neck cancer and tobacco abuse, Tuyns et al. [5] found a relative risk of 12.5 for hypopharyngeal carcinoma with a consumption of 121 g alcohol/day, 10.6 for epilaryngeal carcinomas, 2.0 for supraglottic laryngeal carcinomas and 3.4 for glottic and subglottic carcinomas. Brugere et al. [25] found higher relative risks with an alcohol consumption of 100–159 g/day: oral/tongue carcinomas 13.1; oropharyngeal carcinomas 15.2, and hypopharyngeal carcinomas 28.6. With a consumption of 1160 g/day, the relative risk increases even more (oral cancer 70; oropharyngeal cancer 70, and hypopharyngeal cancer 143) [25]. Gronbaek et al. [33] established an increasing risk for head and neck cancer with increasing alcohol consumption as they were able to show an 11.7-fold increase in the occurrence of head and neck cancer with the consumption of alcohol.

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Abstention/Abuse and Relative Risk of Head and Neck Cancer

Further evidence implicating alcohol as a pathogenic factor for head and neck tumors comes from several studies of people that traditionally abstain from alcohol [34]. Certain religious groups, such as the Seventh-Day Adventists and Mormons, usually abstain from alcohol by church proscription and therefore provide researchers with opportunities to study the effect of alcohol drinking on cancer incidence and mortality [7]. A lower than expected incidence of head and neck cancer has been reported for those religious groups compared with the general population [35]. Wynder et al. [22] found that the frequency of cancer of the mouth, larynx and esophagus among Seventh-Day Adventists was only 13% of that seen among non-Adventists. Other studies conﬁrmed that there was a decreased risk of oral, pharyngeal and esophageal cancers among California Seventh-Day Adventists, based on mortality data. Cancer incidence and mortality among Mormons have also been studied. In Utah, where detailed cancer incidence rates are available, the incidence of cancer of the oral cavity, pharynx, esophagus and larynx was 20–40% among Mormons compared with non-Mormons [36]. In California, mortality rates among Mormon men were 53% for oral-pharyngeal, 45% for esophageal and 30% for laryngeal cancer, compared with the general population of the USA [37]. Even lower risks for these cancer sites were observed among active Mormons abstaining almost completely from the use of alcohol [37]. Another option to investigate the effect of alcohol intake on cancer incidence and mortality is to look at alcoholics. Alcoholics, by deﬁnition, are addicted to excessive use of alcohol. Their cancer mortality and incidence rates have been studied in several countries and compared with the prevailing rates in the general population [38]. A 3- to 6-fold increased risk of head and neck cancer compared with the general population was reported for these alcoholics, the risk tended to be higher for oral and pharyngeal cancers than for laryngeal cancer. Cohort studies, looking at alcoholics in Norway, Sweden, Canada and the USA, have found an increased risk for oral cancer compared with the general population [7, 25]. Alcoholics were found to have signiﬁcantly more cancer cases than controls; the incidence for head and neck cancer was higher in the alcoholic group compared with the general population and that alcoholics with head and neck cancer were heavy drinkers and smokers for signiﬁcantly longer periods of time than alcoholics without head and neck abnormalities [39]. Brewery workers are also

Riedel/Goessler/Hörmann

presumed to drink a larger amount of beer than the general population. In cohort studies of brewery workers in Dublin, Denmark and Sweden, a relatively small but statistically signiﬁcant increase in the risk of head and neck cancer was found compared with the general population [40–42].

Type of Alcoholic Beverages

Ethanol is present in alcoholic beverages as a consequence of the fermentation of carbohydrates with yeast. Beside ethanol, beer, wine and spirits also contain volatile and non-volatile ﬂavor compounds. Although the term ‘volatile compound’ is rather diffuse, most of the compounds that occur in alcoholic beverages can be grouped according to whether they are distilled with alcohol and steam, or not. Volatile compounds include aliphatic carbonyl compound, alcohols, monocarboxylic acids and their esters, nitrogen- and sulfur-containing compounds, hydrocarbons, terpenic compounds and heterocyclic and aromatic compounds. Non-volatile extracts of alcoholic beverages comprise unfermented sugars, di- and tribasic carboxylic acids, coloring substances, tannic and polyphonic substances and inorganic salts [for review, see 8, 11]. The type of alcoholic beverage has been regarded as signiﬁcant, the results in the literature are often controversially discussed. The results of a case-controlled study suggested that beer or wine drinkers had a much higher relative risk for the development of head and neck cancer than whisky drinkers [28]. Whisky drinkers consuming greater than 10 whisky equivalent units/day had a relative risk of 7.3 whilst wine or beer drinkers had a relative risk of 20.4 [28]. In contrast to these results, beer and whisky have been implicated over wine [43] and whisky has been implicated over beer and wine [44] in other studies. Leclerc et al. [45] found that in cases of oral cancer a higher proportion of wine consumers were observed. Speciﬁc alcoholic beverages have been shown to contain speciﬁc impurities or contaminants which were found to be carcinogenic. For example, N-nitrosodiethylamine is present in some beers and whisky and has been associated with an increased risk of head and neck cancer [46]. Carcinogenic polycyclic aromatic hydrocarbons have been found in many brands of whisky [47]. Summarizing all the results, it seems that the total amount of alcohol [7] and the duration of alcohol consumption [39] are regarded to be more important factors than the type or constitution of alcoholic beverage consumed.

Alcohol-Related Diseases of the Mouth and Throat

Metabolism of Ethanol

Alcohol dehydrogenase (ADH), microsomal ethanol oxidizing system and catalase are the most important enzymes involved in the metabolism of ethanol [8, 11]. Most alcohol is metabolized by ADH to acetaldehyde. It has been proposed that the major part of the carcinogenic potency of alcohol is mediated via this compound [48]. There is increasing evidence for acetaldehyde to be the ultimate carcinogenic substance behind alcohol consumption. Acetaldehyde has been shown to be highly toxic, mutagenic and carcinogenic in different cell cultures and animal models [49–51]. In experimental animal studies, histopathological changes after acetaldehyde treatment have been shown to mimic those known to occur after treatment with alcohol [52]. Stronger evidence for acetaldehyde as the major factor behind ethanol-associated carcinogenesis is derived from studies linking the genotypes of ethanol-metabolizing enzymes with tumor risk. Rapid metabolizing ADHs (ADH3), leading to higher and quicker production of cellular acetaldehyde, and lack of the low Km aldehyde dehydrogenases (ALDHs) ALDH2, leading to a longer and delayed exposure to acetaldehyde, have recently been shown to be associated with increased cancer risk in the upper gastrointestinal tract [53–57]. Various ALDH isoenzymes exist throughout the body, e.g. gastrointestinal tract, kidneys, lungs, etc., which can show genetic variations [58]. ADH and ALDH activity has been demonstrated in the oral cavity [59]. Interestingly, the activity of the ALDH is much less than that of the ADH [60]. This would suggest that it is possible for the cytotoxic acetaldehyde to accumulate in the oral tissues and may thus be a factor in alcohol-related oral disease.

Alcohol Effect on Oral Mucosa

Experimental work has also been carried out to look at morphological changes in the oral mucosa. Mascres et al. [61] looked at the effect on rat esophageal mucosa of chronic ethanol exposure. They observed epithelial atrophy following chronic alcohol consumption. The atrophy was due to a decrease in basal cellular size. Müller et al. [62] compared the effects of acute and chronic alcohol exposure on oral mucosa in a rabbit animal model. Over the short term, they observed varying degrees of tissue damage depending on the concentrations of alcohol used. In the long term, they observed dysplastic changes with keratosis, increased density of the basal cell layer and a

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197

ALCOHOL

ORAL MICROBES

MUCOSA

SALIVA

Ac c umulation of pathogenic bac teria

C ell damage

Atrophy of Glandular ac ini

C ell regeneration

Sec retion Vis c os ity

Inflammation

Genetic c hanges C ontac t time of carcinogens

Fig. 1. Effect of alcohol on oral microbes, oral mucosa and salivary glands.

slightly increased number of mitotic ﬁgures. Maier et al. [63] also looked at the effects of chronic ethanol consumption on the oral mucosa in a rat animal model. They observed a signiﬁcant increase in the size of the basal cell layer and basal cell nuclei of oral epithelium and an increase in the percentage of cells in the S-phase of the cell cycle. The mean epithelial thickness was reduced. They suggested that the chronic ethanol consumption caused oral mucosal atrophy with associated hyper-regeneration, which in turn may result in an enhanced susceptibility of the mucosal epithelium towards chemical carcinogens. The underlying mechanisms of the increased proliferative activity of the mucosal epithelium of the oral cavity are still unclear, but it is believed that this hyper-regeneration might be caused by a cytotoxic effect of ethanol. Further, in previous animal experiments [63] and in human post-mortem studies [64] it has been shown that chronic ethanol consumption besides hyper-regeneration also causes atrophy of the oral and pharyngeal mucosa. Atrophy not only occurs in tissues in direct contact with ethanol such as the oral and the pharyngeal mucosa. Thus, it appears likely that ethanol not only exerts a local toxic effect on the epithelium of the upper aerodigestive tract, but also interferes systemically with the metabolism of mucosal cells. Another pathway by which alcohol may affect the oral mucosa is through a direct effect of ethanol on the phospholipid bilayer of the cell membrane. The idea is that if the oral mucosa is exposed to a solvent such as alcohol which removes some of the lipid

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content, the mucosa becomes considerably more permeable. This might lead to an increased penetration of carcinogens across the oral mucosa [5, 8, 11]. Ethanol has also been shown to enhance the penetration of the tobacco carcinogen nitrosonornicotine across the oral mucosa [66]. In addition, Howie et al. [67] also demonstrated an increase in the permeability of the human tongue in vitro to high molecular weight molecules in the presence of alcohol.

Alcohol Effect on Oral Microbes

As described above, smoking and chronic alcohol consumption can affect and decrease saliva ﬂow (ﬁg. 1) [6, 8, 11]. In the presence of a low saliva ﬂow it is known that bacterial concentrations increase, and this might be an explanation for the higher total counts in these subjects [48]. However, also qualitative changes in the microbial ﬂora in high acetaldehyde producers are detectable, as already described for smokers [48]. For instance, high acetaldehyde producers were shown to have an increased incidence of Candida albicans [48]. In general, a microbial ‘switch’ with a signiﬁcant increase in the proportion of Gram-positive versus Gram-negative bacteria has been described in smokers [68–71]. This is in line with the results of Homann et al. [48] that almost all aerobic Grampositive bacteria were signiﬁcantly increased in ‘high’ acetaldehyde producers, with the facultative commensals

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Staphylococcus sp. and Streptococcus mutans as the only exceptions. Gram-negative aerobic bacteria such as Haemophilus sp. and Neisseria sp. were not associated with higher acetaldehyde production. Microbial changes in the oral microﬂora of alcoholics have been less intensively described [72]. Epidemiological studies have shown that heavy drinking is associated with poor oral hygiene. It has been suggested that this may lead to bacterial overgrowth, but so far no study has convincingly proved this hypothesis and no bacterial species have been associated with high alcohol consumption [48, 72]. As high salivary acetaldehyde production was observed only among heavy drinkers, enzyme induction might be an explanation for this ﬁnding. Bacteria are known to be easily able to induce the corresponding metabolizing enzymes [48]. As mentioned above, there is epidemiological evidence indicating that alcohol has tumor-promoting effects [1–8, 10, 11, 73, 74]. The pathogenic mechanism of alcohol intake behind the epidemiological ﬁndings could be the local production of carcinogenic acetaldehyde from ethanol by oral microbes. In a very recent study among Orientals, a possible correlation between ALDH2 genotype mutation and cancer risk in alcoholics has been expanded to all possible alcohol-related cancers. In this study, the frequency of a mutant ALDH2-2 allele was signiﬁcantly higher in alcoholics with oropharyngeal, laryngeal, esophageal, stomach, colon and lung cancer, but not liver or other cancers [55]. This is very interesting, as these organs are covered by microbes and microbial production of acetaldehyde from ethanol has been described [75–78]. Thus, it is possible that the hampered detoxiﬁcation of acetaldehyde from ethanol in ALDH2-deﬁcient subjects might only become clinically relevant in cases of marked acetaldehyde production by microbes. Hence, there is conclusive experimental support for microbial acetaldehyde production from ethanol as a major factor in alcohol-associated carcinogenesis [48].

Alcohol Effect on Saliva and Salivary Glands

Clinical enlargement of the parotid gland is often present in chronic alcoholics [79, 80]. Investigating the effect of chronic ethanol consumption on salivary gland morphology and function in a rat animal model, Maier et al. [81] found fat accumulation in acinar cells along with a reduction in weight and protein content of the parotid gland. Maier et al. [81] also demonstrated a re-

Alcohol-Related Diseases of the Mouth and Throat

duction in salivary ﬂow rates based on experiments in their animal model. This reduction in salivary ﬂow might be due to salivary gland atrophy [81]. Simanowski et al. [65] suggested that a decrease in salivary ﬂow would lead to a decreased clearing of mucosal surfaces. This could lead to an accumulation and consequently to an increased exposure of the oral mucosa to carcinogens [82]. Other investigations based on in vitro analysis demonstrated a reduction in mutagenic activity of some carcinogens by human saliva [83, 84]. Recently, local acetaldehyde production in the saliva by microbes has been described [85]. The same group recently investigated the factors that regulate the microbial production of acetaldehyde in saliva. Moreover, possible differences in microbial composition and relative concentrations among ‘high’ and ‘low’ acetaldehyde producers were examined [48]. The group demonstrated that smoking and heavy alcohol consumption signiﬁcantly increase salivary acetaldehyde production. While smoking showed a positive linear correlation, alcohol seems to interact and increase salivary acetaldehyde production only if consumption is heavy (140 g/day); but when an increase is observed, it is dose-dependent. Smoking and alcohol together increase salivary acetaldehyde production by 100% as compared with non-smokers and moderate alcohol consumers. It was concluded that these ﬁndings could be a biologically plausible mechanism to explain the synergistic and multiplicative manner by which the attributable cancer risks of alcohol and smoking act [48]. Microbial salivary acetaldehyde production shows high inter-individual variation, but there exists a signiﬁcant positive correlation between salivary ethanol and acetaldehyde levels. Moreover, in vivo salivary acetaldehyde levels correlate very signiﬁcantly with the levels that are produced in vitro. This offers the opportunity to use the in vitro salivary test as a tool to investigate possible variables which might inﬂuence salivary acetaldehyde production. Salivary acetaldehyde levels after ethanol intake strikingly exceed those known to be derived from endogenous metabolism of ethanol [85]. Via normal distribution and evaporation, salivary acetaldehyde may reach all target tissues of the upper aerodigestive tract. Consequently, it is suggested that the major part of the carcinogenic role of alcohol is caused by its ﬁrst metabolite, acetaldehyde, which is microbially produced [48].

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199

Alcohol Effect on DNA Repair Mechanisms

Several authors have suggested that alcohol may have an effect on DNA repair mechanisms [8, 11, 86, 87]. Some experiments have demonstrated that chronic ethanol consumption interferes with the repair of alcylated DNA [88, 89]. An increased risk for the development of head and neck cancer associated with combined increased chromosome sensitivity and increased alcohol consumption has been demonstrated. This suggested that the DNA repair capacity was inhibited, increasing susceptibility to environmental carcinogens such as alcohol [8, 11]. Hsu and Furlong [17] looked at the effects of pulsed bleomycin with the addition of different concentrations of alcohol in vitro. After a bleomycin pulse with incubation in 0.5% alcohol, the frequencies of chromatid breaks steadily dropped as incubation time increased, but if 2% alcohol was used, the number of chromosome breakages remained high, suggesting that DNA repair was inhibited. This inhibition phenomenon was reversed when ethanol was removed from the growth medium [8, 11, 17].

Alcohol Effect on Genotoxicity

Alcohol has been shown to potentate the genotoxicity of mutagenic/clastogenic/carcinogenic agents [8, 11]. Hamsters whose cheek pouches were painted with the carcinogen dimethylbenzanthracene (DMBA) and alcohol developed epithelial tumors earlier and larger than those painted with DMBA alone [90]. Lin et al. [91] have demonstrated in vitro that the clastogenicity of ultraviolet light and cytotoxic drugs is potentiated by treatment with alcohol. Hsu [92] also looked at different mutagenic agents in vitro, and found that concurrent addition of alcohol increased the clastogenicity of all agents tested. In another in vitro experiment, Patel et al. [93] demonstrated that the clastogenicity of the genotoxic agent pan masala was potentiated by alcohol.

found to be associated with an increased risk of death, whereas abstinence (for at least 1 year prior to cancer diagnosis) was associated with a decreased risk of death [8, 11, 94]. One reason for this might be the effect of chronic alcohol consumption on the liver’s ability to deal with toxic or potentially carcinogenic compounds [8, 11, 24, 95, 96]. In addition to metabolic systemic effects, the immunosuppressive effects of alcohol [8, 11, 85], including T-cell depression and decreased cytotoxicity of natural killer cells, might contribute to the worse prognosis of alcoholics compared to non-alcoholics. Beside that, alcohol consumption resulted in an increased number of chromosomal aberrations and sister chromatid exchange frequency in lymphocytes in a rat animal model [97]. These data support the hypothesis that the co-carcinogenic activity of ethanol may not be limited to local effects, but through systemic effects associated with chronic alcohol consumption. For example, it is known that alcoholics are not infrequently malnourished [98]. Valin et al. [99] showed in vitro endogenous nitrosation of alcohol-related metabolites to produce mutagenic substances. The carcinogenicity of N-nitropyrrolidine, a tobacco-related carcinogen, has been shown to be enhanced in vivo in an animal model by chronic ethanol administration [24]. Investigating various alcoholic beverages, Yamada et al. [100] found DNA methylation to be increased in the esophagus after alcohol administration. They concluded that the beverages tested in this study may contain congeners which may themselves or in synergy cause a shift in nitrosamine metabolism from the liver to extra-hepatic tissues. Comparing the effect of ethanol on the metabolism of nitrosamine in different organs, Swann et al. [101] demonstrated a reduction in nitrosamines in ﬁrstpass clearance in the liver, which led to an increased metabolism in extrahepatic tissues. Their results suggest that the role of ethanol in carcinogenesis may be through its different effects on nitrosamines from tobacco smoke, diet and endogenous sources [101].

Conclusions Alcohol and Its Systemic Effects

Deleyiannis et al. [94] investigated the prognosis of patients with head and neck cancer depending on alcohol consumption. They were able to show that patients who were alcoholics have a poorer prognosis than non-alcoholic patients. They suggested that this is in part due to an increased risk for other alcohol-related diseases. Alcoholism and a history of alcohol-related disorders were

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Chronic consumption of alcoholic beverages is an accepted social custom worldwide. In the upper aerodigestive tract, local morphologic, metabolic and functional alterations are present due to alcohol consumption. Epidemiological data clearly indicate an independent carcinogenic effect of alcohol intake. A dose-effect relationship between alcohol consumption and the incidence of head and neck carcinomas has been found. An increased

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risk of head and neck cancer compared with the general population was reported for alcoholics. The total amount of alcohol and the duration of alcohol consumption seem to be more important factors than the type or constitution of the alcoholic beverage consumed. The pathogenetic mechanisms of chronic alcohol consumption might be the local production of carcinogenic acetaldehyde from ethanol by oral microbes.

Acknowledgements This work was supported by grants from the Research Fund of the Faculty of Medicine Mannheim, University of Heidelberg, and the ‘Landesforschungsschwerpunkt Alkohol und Alkoholfolgekrankheiten’ of the State of Baden-Württemberg, Germany.

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74 Mashberg A, Garﬁnkel L, Harris S: Alcohol as a primary risk factor in oral squamous carcinoma. CA Cancer J Clin 1981;31:146–155. 75 Jokelainen K, Heikkonen E, Roine R, et al: Increased acetaldehyde production by mouthwashings from patients with oral cavity, laryngeal or pharyngeal cancer. Alcohol Clin Exp Res 1996;20:1206–1210. 76 Jokelainen K, Siitonen A, Jousimies-Somer H, et al: In vitro alcohol dehydrogenase-mediated acetaldehyde production by aerobic bacteria representing the normal colonic ﬂora in man. Alcohol Clin Exp Res 1996;20:967–972. 77 Miyakawa H, Baraona E, Chang JC, et al: Oxidation of ethanol to acetaldehyde by bronchopulmonary washings: role of bacteria. Alcohol Clin Exp Res 1986;10:517–520. 78 Pikkarainen PH, Baraona E, Jauhonen P, et al: Contribution of oropharynx ﬂora and of lung microsomes to acetaldehyde in expired air after alcohol ingestion. J Lab Clin Med 1981;97: 631–636. 79 Mandel L, Baurmash H: Parotid enlargement due to alcoholism. J Am Dent Assoc 1971;82: 369–373. 80 Abelson DC, Mandel ID, Karmiol M: Salivary studies in alcoholic cirrhosis. Oral Surg Oral Med Oral Pathol 1976;41:188–192. 81 Maier H, Born IA, Veith S, et al: The effect of ethanol consumption on salivary gland morphology and function in the rat. Alcohol Clin Exp Res 1988;10:425–429. 82 Graham S, Dayal H, Rohrer T, et al: Dentition, diet, tobacco, and alcohol in the epidemiology of oral cancer. J Natl Cancer Inst 1977; 59: 1611–1618. 83 Nishioka H, Nishi K, Kyokane K: Human saliva inactivates mutagenicity of carcinogens. Mutat Res 1981;85:323–333. 84 Stich HF, Rosin MP, Bryson L: The inhibitory effect of whole and deproteinized saliva on mutagenicity and clastogenicity resulting from a model nitrosation reaction. Mutat Res 1982; 97:283–292. 85 Homann N, Jousimies-Somer H, Jokelainen K, et al: High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis 1997;18:1739–1743. 86 Hsu TC, Furlong C, Spitz MR: Ethyl alcohol as a cocarcinogen with special reference to the aerodigestive tract: a cytogenetic study. Anticancer Res 1991;11:1097–1101. 87 Mufti SI: Alcohol acts to promote incidence of tumors. Cancer Detect Prev 1992; 16: 157– 162. 88 Garro AJ, Espina N, Farinati F, et al: The effects of chronic ethanol consumption on carcinogen metabolism and on O6-methylguanine transferase-mediated repair of alkylated DNA. Alcohol Clin Exp Res 1986; 10: 73S– 77S. 89 Mufti SI, Salvagnini M, Lieber CS, et al: Chronic ethanol consumption inhibits repair of dimethylnitrosamine-induced DNA alkylation. Biochem Biophys Res Commun 1988; 152:423–431.

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98 Harris CK, Warnakulasuriya KA, Johnson NW, et al: Oral health in alcohol misusers. Community Dent Health 1996;13:199–203. 99 Valin N, Haybron D, Groves L, Mower HF: The nitrosation of alcohol-induced metabolites produces mutagenic substances. Mutat Res 1985;158:159–168. 100 Yamada Y, Weller RO, Kleihues P, et al: Effects of ethanol and various alcoholic beverages on the formation of O6-methyldeoxyguanosine from concurrently administered N-nitrosomethylbenzylamine in rats: a doseresponse study. Carcinogenesis 1992; 13: 1171–1175. 101 Swann PF, Coe AM, Mace R: Ethanol and dimethylnitrosamine and diethylnitrosamine metabolism and disposition in the rat. Possible relevance to the inﬂuence of ethanol on human cancer incidence. Carcinogenesis 1984;5:1337–1343.

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Table 1. Effects of acute and chronic ethanol consumption on esophageal motility [1–12]

Parameter

Tonus of the lower esophageal sphincter Tubulary contractions

Esophageal clearance Number of reﬂuxes

Acute effects (healthy humans)

Chronic effects (alcoholics)

Decreased Decreased amplitudes and propagation Increase in double-peaked and simultaneous contractions Decreased Increased

Increased, normalization during abstinence Increase in higher amplitudes and simultaneous, repetitive contractions Prolongation of each contraction, no normalization during abstinence Decreased, normalization during abstinence No data

For a detailed description see text.

quency of gastroesophageal reﬂux (by up to 90%) and in a prolongation of each reﬂux episode by diminishing esophageal clearance (table 1) [5, 6]. These effects are dose-dependent and start with a threshold dose of 45– 60 g ethanol or at blood ethanol concentrations of 70– 90 mg/dl [7]. Chronic ethanol consumption is frequently associated with secondary motility disorders of the distal esophagus: prolonged contractions of pathologically high amplitudes and simultaneous or double-peaked contractions. The effect on the lower esophageal sphincter is contrary to that of acute ethanol administration. In alcoholics with an average daily ethanol consumption of up to 300 g over many years without evidence of a neuropathy, the following esophageal motility changes were detected: signiﬁcantly higher pressure of the lower esophageal sphincter with normal relaxation after swallow, and reduced esophageal clearance [8–11]. In contrast, in patients with alcoholic peripheral neuropathy the lower esophageal sphincter pressure was not increased [12]. The effects of acute and chronic administration on esophageal motility are summarized in table 1. Esophagitis Alcohol consumption is frequently associated with symptoms of heart burn. The previously described effects on esophageal motility and lower esophageal sphincter tone after alcohol consumption may theoretically facilitate or enforce gastroesophageal reﬂux. However, systemic investigations concerning this matter are still lacking and there are only three epidemiological studies available that demonstrate a relationship. In one study an increase in the prevalence of abnormal histological ﬁndings of the esophageal mucosa was observed in alcoholics [13]. In

Alcohol-Related Diseases of the Esophagus and Stomach

another study 8 of 10 patients with Barrett’s esophagus had an alcohol intake of at least 80 g daily over many years [14]. Additionally, one multicenter case-control study has shown that alcohol consumption may be a possible risk factor in the development of esophagitis and/or Barrett’s esophagus [15]. Besides the induction of esophagitis due to an increased gastroesophageal acid reﬂux, alcohol itself might impair the esophageal mucosa [3–12, 16]. For example, Chung et al. [17] have shown in rabbits that ethanol perfusion (5% v/v adjusted with sodium chloride to a total ionic concentration of 300 mM) markedly increased the rate of removal of H+ from the esophageal lumen with an accompanying fall in the transmural potential difference. These changes were aggravated in the presence of hydrochloric acid. Histologically, ethanol perfusion alone produced mild edema and submucosal vasodilatation. Using an ethanol solution with an H+ concentration of 10 mM or higher resulted in a progressive increase in signs of mucosal injury such as submucosal edema, hemorrhage, polymorphonuclear inﬁltration, and diffuse ulceration [17]. However, these results could not be conﬁrmed in humans and no correlation between the use of alcohol and an increased risk of developing any type of erosive reﬂux esophagitis could be found [18–20]. Cancer It was ﬁrst reported in 1962 that excessive alcohol intake is connected to a higher incidence of esophageal cancer in male patients [21]. More evidence for an association was adduced by case-control studies and cohort studies in which the contribution of alcohol was separated from smoking, a frequently associated risk factor [22–28]. The global burden of esophageal cancer further supports

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205

44.4

19.9 12.3

18.0

8.4

5.1 >20 3.4

7.3

10–19 Number of cigarettes/day

1.0 >8

0–9 4–8

Fig. 1. Risk of developing esophageal can-

0–4 Number of drinks/day

cer as a function of alcohol and tobacco consumption. Adapted from Tuyns et al. [40].

this association [29, 30]. Up to 50–75% of cases of esophageal cancer in both men and women are attributable to the consumption of alcohol [31]. A meta-analysis of all available epidemiologic studies demonstrates an increase in the risk of developing esophageal cancer of 30% with every daily drink (equivalent to 10 g ethanol). Despite the differences in the type of alcoholic beverages consumed, there exists a markedly close dose-response relationship between daily alcohol consumption and the risk of esophageal cancer in different geographical areas [32–36]. It is important to note that there is no threshold under which there is no increase in the risk for cancer. Several studies show that the consumption of distilled spirits results in a greater increase in the risk of cancer than the consumption of the same amount of alcohol in other beverages [37, 38]. The combination of alcohol and tobacco abuse exerts an additive and even a multiplicative effect on the development of esophageal cancer [39] (ﬁg. 1). For example, the relative risk of esophageal cancer in subjects with an intake of 80 g alcohol/day increased from 18 to 44.4 when

206

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20 g tobacco was additionally smoked daily [40]. Alcohol showed a slightly higher attributable risk than smoking (52 vs. 40%) [41]. The synergistic effect of the combination of alcohol and tobacco is important because more than 75% of persons who consume alcohol chronically are smokers. However, contrary to smoking, consumption of fruits and vegetables modestly decreases the risk of cancer [42, 43]. The exact mechanisms by which alcohol beverages cause esophageal cancer in humans have not been determined. Ethanol itself does not induce cancer, but may play a permissive role. It is assumed that congeners in alcohol beverages such as nitrosamines and polycyclic hydrocarbons, acetaldehyde, and solvents, may displace nutrients in the diet, impair nutrient metabolism, inhibit detoxiﬁcation, activate speciﬁc enzymes, alter hormonal status, increase oxidant exposure, suppress immune function, alter membrane ﬂuidity, and increase cellular proliferation [44–46]. Figure 2 shows the possible factors resulting in the development of esophageal cancer in alcoholics.

Franke /Teyssen /Singer

Bacteria Acetaldehyde

Nitrosamine

Carcinogens

Ethanol

Enhanced concentration of localeffective carcinogens and prolongation of their contact with the alcohol induced vulnerable mucosa Motility Reflux

Liver Pro-carcinogen

HCl

Fig. 2. Possible factors resulting in the development of esophageal cancer in alcoholics. Together with gastroesophageal reﬂux ethanol results in chronic inﬂammation of the esophagus. The mucosa becomes more susceptible to carcinogens, such as polycyclic aromatic carbohydrates and nitrosamine. These substances are found in alcoholic beverages or can be produced by pro-carcinogens in the liver. Through the catabolism of ethanol in the liver, degradation of pro-carcinogens is inhibited. In addition, ethanol is metabolized by bacteria in the oral cavity to acetaldehyde.

Effect of Alcohol on the Stomach

Gastric Emptying Almost all studies on the effect of ethanol or alcoholic beverages on gastric motility relate to the gastric emptying rate of the gastric content, since it is the clinically decisive parameter of gastric motility and represents the sum of gastric motor activity. Early studies by Cooke [47] in 1970 found delayed emptying from the stomach with ethanol concentrations of 8 g/100 ml or more (12 and 16 g/100 ml) when compared to water. Franke et al. [48] recently conﬁrmed the inhibitory effect of ethanol and detected inhibition even at low ethanol concentrations (4% v/v; ﬁg. 3). This inhibitory effect by ethanol solutions is not dosedependent [47, 48] and is not induced by their caloric content, since isocaloric glucose solutions have a more pronounced inhibitory effect [48, 49].

Alcohol-Related Diseases of the Esophagus and Stomach

Alcoholic beverages produced by fermentation such as beer and red wine are emptied signiﬁcantly more slowly than their corresponding ethanol concentrations (4 and 10% v/v) [48, 50]. However, whiskey, an alcoholic beverage produced by distillation, inhibits gastric emptying to the same degree as the corresponding ethanol solution (40% v/v). Presumably, the non-alcoholic ingredients in those alcoholic beverages produced by fermentation alone are important additional inhibitory factors [48]. Gastric emptying of a solid meal is regulated differently to the emptying of liquids. Therefore, the gastric emptying rates of ethanol and alcoholic beverages are not naturally transferable to their effect on the emptying of solid meals. Compared to water the gastric emptying of a solid meal is inhibited by ethanol [51, 52], whiskey [53], beer and red wine [52]. Red wine, but not beer, induced a signiﬁcantly slower emptying than the corresponding ethanol solutions (10 and 4%, respectively). No differences regarding the gastric half emptying time of the meal were detected between ethanol solutions and isocaloric glucose, but the slope of gastric emptying was different: whereas the initial lag phase (the period before gastric emptying begins) was prolonged by glucose solutions, the lag phase was nearly unchanged by ethanol or alcoholic beverages. Inversely, the emptying phase was prolonged by ethanol-containing solutions, whereas it was unchanged by glucose. This means that the gastric emptying of meals consumed together with alcohol may begin earlier and then the gastric content may empty more slowly into the duodenum than when consumed with isocaloric glucose solutions [52]. The mechanism by which this is mediated remains to be elucidated. Concerning the chronic effects of alcohol on gastric motility the data are scanty and inconsistent. While Keshvarzian et al. [54] did not detected any effect on the gastric emptying of solid test meals 3–10 days after alcohol abstinence, Wegener et al. [55] found a dose-related inhibitory effect on the gastric emptying rate of solid test meals in actively drinking and symptomatic alcoholics. However, gastric retention may play a role in the development of malnutrition in alcoholics [56]. Gastric Acid Secretion It is about 100 years ago that a stimulatory effect on gastric acid secretion was suggested after uncontrolled experiments with alcohol [57, 58]. Beginning in the early 1980s and using systematic and controlled examinations on the effect of pure ethanol and commonly ingested alcoholic beverages on gastric acid secretion, Singer and

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207

90 a, b

80

a

Gastral half emptying time (t½)

70

60

50 a, b 40 a a 30

a

a

20

10

0

500 ml

250 ml

Fig. 3. Gastric half emptying time (t½) of the test solutions. Results are means 8 SEM of 10 subjects. G = Glu-

cose (w/v); E = ethanol (v/v). Whiskey (125 ml) and E 40% (125 ml) were diluted with 125 ml water. a p ! 0.05 compared with water, b p ! 0.05 compared with the respective pure ethanol solution. Adapted from Franke et al. [48].

5

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3

1 0

–2 1.4

4

5

6

7

8

10

20

40

Ethanol (% v/v)

Franke /Teyssen /Singer

Water

ethanol, distilled water, and glucose on incremental 1-hour gastric acid output. The 7.9, 11.5, 20, and 34.2% (w/v) glucose solutions are equivalent to 1.4, 4, 10, and 20% ethanol (v/v), respectively. Results are mean of 6 subjects. a p ! 0.05 compared with both distilled water and the isotonic glucose control solution. Adapted from Singer et al. [60].

a

Glucose 5.76 %

Fig. 4. Effect of intragastric instillation of

Incremental gastric acid output (mmol/h)

a

a

a

Maleic acid and succinic acid

a

Fermented Glucose (11.5% w/v)

18

a

Incremental gastric acid output (mmol/h)

a

a

15

a a 10

5

Distillation

Beer

Champagner

Wine

Sherry

Martini

Campari

Cointreau

Pernod Fils

Bacardi

Armagnac

Calvados

Cognac

Whiskey

Glucose 5.76%

–4

MAO-pentagastrin

0

Fermentation

Fig. 5. Gastric acid secretion (mmol/h) after instillation of different types of alcoholic beverages (hard liquors, aperitifs, wine, champagne, and beer) compared to the maximal acid output (MAO) of pentagastrin. Results represent means 8 SEM from 6 subjects. a p ! 0.05 for the difference compared with glucose control (5.76% w/v). Adapted from Singer et al. [65].

co-workers [59–67] found that the effect of ethanol and alcoholic beverages on gastric acid secretion in healthy humans is differentiated after all. (1) The effect of pure ethanol is concentration-dependent (ﬁg. 4). Low concentrations (1.4 and 4.0% v/v) have a mild stimulatory effect on gastric acid output (23% of the pentagastrin-stimulated incremental gastric acid output or maximal acid output, MAO). Higher concentrations of pure ethanol (up to 40% v/v) have either no or, if at all, a mild inhibitory effect [60]. None of the ethanol concentrations tested increased plasma gastrin concentrations [60; for reviews, see 68–71]. (2) In contrast, some of the commonly ingested alcoholic beverages produced by fermentation (such as beer and wine; ﬁg. 5) are potent stimuli of gastric acid output as well as the release of gastrin [60, 65]. Oral or gastric

instillation of beer causes stimulation of acid output to 95% of that produced by pentagastrin (MAO). Red and white wines increase the gastric acid output to 61% of MAO. (3) Beverages with a high alcohol content produced by distillation, such as whiskey and cognac (40% v/v), do not stimulate gastric acid output or the release of gastrin [60] (ﬁg. 5). Neither the ethanol content nor the known non-alcoholic components in beer or red wine (for example magnesium, calcium, amines, phenols, amaroids, vitamins, and L-amino acids) were found to be responsible for the stimulatory effect [65]. Teyssen et al. [66] have shown that the substances responsible for the maximal gastric acid secretion in fermented beverages are succinic acid and maleic acid, produced during the process of alcohol-

Alcohol-Related Diseases of the Esophagus and Stomach

Dig Dis 2005;23:204–213

209

Fig. 6. Integrated endoscopic scores over

24 h in the fundus in response to beer, wine, and whiskey and the corresponding ethanol content (4, 10, and 40% v/v) in comparison with the control. The results are expressed as means 8 SEM of 6 subjects and 11 subjects (whiskey). a p ! 0.05 in comparison with the control; b p ! 0.05 in comparison with the corresponding ethanol content. Adapted from Knoll et al. [75].

24-hour integrated endoscopic score in the fundus

5,000

4,000

a

3,000 a 2,000

1,000

a, b b

0 Control

ic fermentation, and that gastrin does not mediate their effect. Alcoholic beverages produced by fermentation followed by distillation, such as most aperitifs and hard liquors, do not stimulate acid secretion (ﬁg. 5) [67]. Acute Gastritits Topical experimental instillation of high concentrations of pure ethanol (40–80% v/v) damages the human gastric mucosa already in the ﬁrst 30 min after application [72–75]. In further studies also lower concentrations of pure ethanol (corresponding to concentrations found in common alcoholic beverages) showed similar effects [75]. Moreover, dose-dependent damage to the gastric mucosa (up to hemorrhagic gastritis) by gastric instillation of pure ethanol was identiﬁed [75]. The lesions occurred within 30 min, and reached a maximum after 60 min. Studying the effect of gastrically instilled alcoholic beverages on the mucosa, it was found that the injuries in response to beer and wine were signiﬁcantly less pronounced than the corresponding ethanol content (ﬁg. 6). In the case of pure ethanol at concentrations higher than 10% and whiskey, the lesions were still present 24 h later. However, no lesions were observed in the duodenum. The lesser damage caused by alcoholic beverages are most probably due to a protective action of unknown non-alcoholic ingredients [75].

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a

a

4

10

40

Beer

Wine

Whiskey

Ethanol (% v/v)

An additionally important risk factor for the development of hemorrhagic erosive gastritis after acute ethanol ingestion is the presence of liver cirrhosis with associated portal hypertension and hypertensive gastropathy [76]. The pathophysiological mechanisms of damage to the gastric mucosa by ingestion of pure ethanol and common alcoholic beverages are not completely understood. The known effects on gastric mucosa are summarized in ﬁgure 7. Chronic Gastritis Although an association between the prevalence of chronic atrophic diffuse corpus or antrum gastritis and chronic alcohol is presumed by some studies [77], no evidentiary data exist in epidemiologic studies when alcohol consumption is separated from other factors. Chronic infection with Helicobacter pylori and not alcohol itself seems to be the major causative agent of chronic gastritis in alcoholic patients [78, 79]. Helicobacter pylori Infections Since H. pylori injures the gastric mucosa, epidemiologic studies were examined to determine whether a relationship between chronic alcohol consumption and the prevalence of H. pylori infection exists. These studies failed to show a relationship. Thus, it remains unknown whether there is an interaction between ethanol effects

Franke /Teyssen /Singer

Ethanol H+ Damage Damageof ofthe themucosal mucosalbarrierand barrier and direct directmucosalinjury mucosal injury

Release Releaseofofinflammatory inflammatorymediators mediators Granulocytes? Granulocytes Reactive oxidizingmetabolites? Reactive oxidizing metabolites Cytokines(e.g. TNF-α) - α) ? Cytokines (e.g. TNF Vasoactivesubstances? Vasoactive substances

Inflammation, Inflammation,vasoconstriction vasoconstriction , ischemia ischemia

Cell death, mucosal damage Fig. 7. Pathophysiology of the effect of ethanol on the gastric mucosa. Ethanol directly and dose-dependently impairs the gastric mucosal barrier. Both acidiﬁcation of the mucosal cells and ethanol itself induce release of inﬂammatory and vasoactive substances. Inﬂammation and vasoconstriction lead to ischemia and mucosal damage. Adapted from Teyssen and Singer [70].

and H. pylori infection at the level of the gastric mucosa. Brenner et al. [80] have shown a protective effect of socalled ‘moderate’ alcohol consumption (!75 g/week) against an active infection with H. pylori. These results were supported by Murray et al. [81] who, in a cross-sectional population study with more than 10,000 subjects, have shown that total alcohol consumption was associated with a small, but not statistically signiﬁcant, decrease in the odds for infection with H. pylori. After adjustment for age, sex, ethnicity, childhood and adult social class, smoking, coffee consumption, and intake of alcoholic beverages other than wine, subjects drinking 3–6 units of wine/week had an 11% lower risk of H. pylori infection compared with those who drank no wine (OR = 0.89, 95% CI = 0.80–0.99). Higher wine consumption was associated with a further 6% reduction in the risk of infection (OR = 0.83, 95% CI = 0.64–1.07). An intake of 3–6 units of beer (but not more) was associated with a similar reduction in the risk of infection when compared to no beer intake (OR = 0.83, 95% CI = 0.75–0.91). Baena et al. [82] studied another coherence of H. pylori infection and alcohol consumption. The daily alcohol

Alcohol-Related Diseases of the Esophagus and Stomach

consumption was the only variable signiﬁcantly associated with the success rate of eradication therapy, with a higher probability of failure in non-consumers (29.9%) than in consumers (12.2%), the adjusted odds ratio was 3.24. Moreover, the eradication was alcohol dose-dependent: 70.1% in abstemious patients, rising to 79.3% in users of 4–16 g of pure ethanol a day, and to 100% in users of 18–60 g daily. These studies indicate that modest consumption of wine and beer may protect against H. pylori infection, and that alcohol consumption may sustain H. pylori therapy in a dose-dependent manner. Peptic Ulcer Disease Patients with peptic ulcer disease are often advised to avoid alcoholic beverages. However, retrospective epidemiologic studies conclude that both acute and chronic alcohol consumption are not associated with an increase in the risk of a gastric or duodenal ulcer [83–86]. In two recent large prospective studies no association could be found between the incidence of peptic ulcer disease and the ethanol content or type of alcohol beverage consumed (such as beer, wine or hard liquors) [85, 86]. Until now, there is only one study to support a significant effect of chronic alcohol intake on the incidence of duodenal ulcers. Piper et al. [87] were able to show that ethanol consumption of 60 g daily resulted in a 3.3-fold increase in the risk of duodenal ulcer development (odds ratio 1.8). The incidence of gastric ulcers was not elevated in this study, similarly to other studies [88–91]. Gastric Cancer In more than 40 epidemiologic – mostly retrospective – studies no association between gastric carcinoma and chronic alcohol consumption was found. This is also valid for consumption of large amounts of alcohol (more than 200 g daily). Moreover, the type of alcoholic beverage consumed and its ethanol concentration have no impact either [31, 70, 92–96]. The data on the risk of carcinoma of the cardia are inconclusive. In one representative prospective study, which was adjusted for the effects of age and cigarette smoking, the relation between alcohol consumption and the subsequent occurrence of the ﬁve most frequent cancers in 8,006 Japanese men in Hawaii (cancer of the stomach, colon, rectum, lung, and prostate), no signiﬁcant positive relation between alcohol consumption and the incidence of cancer of the stomach was found regardless of the amount of consumed alcohol and the kind of alcoholic beverage [96].

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211

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67 Teyssen S, Lenzing T, González-Calero G, Korn A, Riepl RL, Singer MV: Alcoholic beverages produced by alcoholic fermentation but not by distillation are powerful stimulants of gastric acid secretion in humans. Gut 1997;40: 49–56. 68 Chari ST, Teyssen S, Singer MV: Alcohol and gastric acid secretion in humans. Gut 1993;34: 843–847. 69 Chari ST, Teyssen S, Singer MV: What controls should be used in studies of acute effects of alcohol and alcoholic beverages on the stomach and the pancreas? Scand J Gastroenterol 1993;28:289–295. 70 Teyssen S, Singer MV: Alkohol und Magen; in Singer MV, Teyssen S (eds): Alkohol und Alkoholfolgekrankheiten. Heidelberg, Springer, 1999, pp 168–187. 71 Singer MV: Effect of ethanol and alcoholic beverages on the gastrointestinal tract in humans. Rom J Gastroenterol 2002;11:197–204. 72 Gottfried EB, Korsten MA, Lieber CS: Alcohol-induced gastric and duodenal lesions in man. Am J Gastroenterol 1978;70:587–592. 73 Laine L, Weinstein WM: Histology of alcoholic hemorrhagic gastritis: a prospective evaluation. Gastroenterology 1988;94:1254–1262. 74 Palmer ED: Gastritis: a re-evaluation. Medicine 1954;33:199–290. 75 Knoll MR, Kölbel CB, Teyssen S, Singer MV: Action of pure ethanol and some alcoholic beverages on the gastric mucosa in healthy humans: a descriptive endoscopic study. Endoscopy 1997;29:1–9. 76 Sarfeh IJ, Tabak C, Eugene J, Juler GL: Clinical signiﬁcance of erosive gastritis in patients with alcoholic liver disease and upper gastrointestinal hemorrhage. Ann Surg 1981; 194: 149–154. 77 Bienia A, Sodolski W, Luchowska E: The effect of chronic alcohol abuse on gastric and duodenal mucosa. Ann Univ Mariae Curie Sklodowska 2002;57:570–582. 78 Uppal R, Lateef SK, Korsten MA, Paronetto F, Lieber CS: Chronic alcoholic gastritis. Roles of alcohol and Helicobacter pylori. Arch Intern Med 1991;151:760–764. 79 Segawa K, Nakazawa S, Tsukamoto Y, Goto H, Yamao K, Hase S, Osada T, Arisawa T: Chronic alcohol abuse leads to gastric atrophy and decreases gastric secretory capacity: a histological and physiological study. Am J Gastroenterol 1988;83:373–378. 80 Brenner H, Rothenbacher D, Bode G, Adler G: Relation of smoking and alcohol and coffee consumption to active Helicobacter pylori infection: cross sectional study. BMJ 1997; 315: 1489–1492. 81 Murray LJ, Lane AJ, Harvey IM, Donovan JL, Nair P, Harvey RF: Inverse relationship between alcohol consumption and active Helicobacter pylori infection: the Bristol Helicobacter project. Am J Gastroenterol 2002; 97: 2750– 2755.

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82 Baena JM, Lopez C, Hidalgo A, Rams F, Jimenez S, Garcia M, Hernandez MR: Relation between alcohol consumption and the success of Helicobacter pylori eradication therapy using omeprazole, clarithromycin and amoxicillin for 1 week. Eur J Gastroenterol Hepatol 2002;14:291–296. 83 Paffenbarger RS Jr, Wing AL, Hyde RT: Chronic disease in former college students. XIII. Early precursors of peptic ulcer. Am J Epidemiol 1974;100:307–315. 84 Friedman GD, Siegelaub AB, Seltzer CC: Cigarettes, alcohol, coffee and peptic ulcer. N Engl J Med 1974;290:469–473. 85 Kato I, Nomura AMY, Stemmermann GN, Chyou PH: A prospective study of gastric and duodenal ulcer and its relation to smoking, alcohol, and diet. Am J Epidemiol 1992; 135: 521–530. 86 Johnson R, Forde OH, Straume B, Burhol PG: Aetiology of peptic ulcer: a prospective population study in Norway. J Epidemiol Community Health 1994;48:156–160. 87 Piper DW, Nasiry R, McIntosh J, Shy CM, Pierce J, Byth K: Smoking, alcohol, analgesics, and chronic duodenal ulcer. A case control study of habits before ﬁrst symptoms and before diagnosis. Scand J Gastroenterol 1984;19: 1015–1021. 88 Piper DW, McIntosh JH, Greig M, Shy CM: Environmental factors and chronic gastric ulcer. A case control study of the association with the exacerbation of chronic gastric ulcer. Scand J Gastroenterol 1982;17:721–725. 89 Würsch TG, Hess H, Walser R, Koelz HR, Pelloni S, Vogel E, Schmid P, Blum AL: Die Epidemiologie des Ulcus duodeni. Untersuchungen an 1015 Patienten in Zürich. Dtsch Med Wochenschr 1978;103:613–618. 90 Friedman GD, Siegelaub AS, Seltzer C: Cigarettes, alcohol, coffee and peptic ulcer. N Engl J Med 1979;290:469–473. 91 Ostensen H, Gudmundsen TE, Ostensen PG, Burhol PG, Bonnevie O: Smoking, alcohol, coffee, and familial factors: any association with peptic ulcer disease? Scand J Gastroenterol 1985;20:1227–1235. 92 Thomas DB: Alcohol as a cause of cancer. Environ Health Perspect 1995;103(suppl 8):153– 160. 93 Boeing H: Epidermal research in stomach cancer: progress over the last ten years. J Cancer Res Clin Oncol 1991;117:133–143. 94 Falcao JM, Dias JA, Miranda AC, Leitao CN, Lacerda MM, Cayolla da Motta L: Red wine consumption and gastric cancer in Portugal: a case-control study. Eur J Cancer Prev 1994;3: 269–276. 95 Jedrychowski W, Boeing H, Wahrendorf J, Popiela T, Tobiasz-Adamczyk B, Kulig J: Vodka consumption, tobacco smoking and risk of gastric cancer in Poland. Int J Epidemiol 1993; 22:606–613. 96 Pollak ES, Nomura AMY, Heilbrunn LK, Stemmermann GN, Green GB: Prospective study of alcohol consumption and cancer. N Engl J Med 1984;310:617–626.

213

5

Blood ethanol concentration (mmol/l)

There is also a concentration gradient of ethanol from the lumen to the blood. The ethanol concentration within the lumen of the jejunum and duodenum is much higher than blood ethanol concentration (BEC) [2]. Alcohol diffuses passively across the cell membranes of the mucosal surface into the submucosal space and then the submucosal capillaries [1]. However, the concentration of ethanol within the lumen of ileum is not signiﬁcantly different from BEC. This suggests that ethanol enters the ileum and colon from the blood and the luminal effects of ethanol ingestion occur mainly in the upper small intestine [3].

Intravenous dosing in normal subjects and patients with Bilroth II subtotal gastrectomy Oral dosing in patients with Bilroth II subtotal gastrectomy Oral dosing in normal subjects

4

3

2

1

0 0

30

Metabolism of Ethanol in the Small Intestine In many tissues the damaging effects of ethanol are due to the metabolite acetaldehyde. However, alcohol dehydrogenase activity is low in the small intestine [4] and BEC is similar after administration of 0.15 g/kg ethanol either intravenously or into the jejunum of gastrectomized patients (ﬁg. 1) [6]. Therefore, the metabolism of ethanol in the small intestine is insigniﬁcant. Effect of Ethanol on Small Intestinal Morphology Acute administration of alcohol results in hemorrhagic erosions of the epithelium at the tips of villi, villus core contraction and compaction, compression of lacteals, separation of the epithelium from the basal lamina of the villus core and formation of subepithelial blisters which ultimately cause rupture of the epithelium [4, 5]. The extent of these morphological changes depends on the concentration, duration of ethanol exposure, speciesdependent sensitivity of the mucosa to injury in animal studies, and the nutritional status of the subject [3, 4, 7]. However, recovery is rapid, occurring even during con-

Effect of Alcohol Consumption on the Gut

90

120

150

180

Time (h)

Small Intestine

The major functions of the small intestine, digestion, absorption and secretion, are performed by the brush border membrane (BBM) and depend on the structural integrity of the intestine in vivo. Peristalsis which gradually propels chyme through the intestine requires coordinated smooth muscle function. The microcirculation supplies essential nutrients. The physiological regulation of the GIT is complex, and neural and hormonal impulses as well as factors secreted by the local immune system are involved. Ethanol-induced GI injury results from a complex interaction of several damaging effects on each of these functional elements [3–5].

60

Fig. 1. Blood ethanol concentration curve after dosing 0.15 g/kg

ethanol. The difference between oral and intravenous dosing represents ﬁrst-pass metabolism. First-pass metabolism is abolished in patients with Bilroth II subtotal gastrectomy. Adapted from Caballeria et al. [6].

Table 1. Ethanol concentrations in the gut and blood after intake

of ethanol (0.8 g/kg body weight) Site

Ethanol concentration, g/dl

Stomach Jejunum Ileum Blood (after distribution, 15–120 min after dosing)

6.5–9.4 6.5–9.4 0.1–0.2 0.1–0.2

Ethanol appears in the blood 5 min after ingestion and is rapidly distributed around the body. A dose of 0.8 g ethanol/kg body weight should produce a blood ethanol concentration of 0.1–0.2 g/ dl 15–120 min after dosing. The highest blood ethanol concentrations occur after 30–90 min. Adapted from Halsted et al. [2].

tinuous exposure to ethanol and probably represents reattachment of healthy epithelial cells to the normal basal lamina [4]. Regeneration could occur by rapid migration of viable epithelial cells originating from cells adjacent to the exfoliated ones as a similar mechanism of regeneration has been reported in the small intestine during mucosal injury from other agents [4]. Chronic ethanol exposure does not necessarily produce the ﬂorid hemorrhagic changes seen with acute ingestion.

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215

The results of studies in both humans and animals are conﬂicting. Chronic alcohol consumption results in shortening and reduced surface area of the villi [3, 5, 8]. This is associated with a hyperproliferation of crypt cells [8]. However, ethanol has also been shown to reduce enterocyte turnover in the crypts [9], possibly due to an inhibition of mitosis related to folate deﬁciency [5]. However, on abstinence the heights of the villi return to normal [5]. These effects may be due to a direct toxic effect of alcohol on the mucosa [3, 4]. However, the effects of ethanol on the microcirculation [10] or immune cells may also be implicated. Effect of Ethanol on Small Intestinal Microcirculation In the small intestine alcohol increases the perfusion of and arterial inﬂow to the mucosa and submucosa but not the muscularis and serosa [11]. Studies of the mucosal microcirculation have demonstrated that interstitial edema and cellular injury can occur if increased mucosal blood ﬂow is associated with a blockage to outﬂow [10]. Blister formation, followed in some cases by epithelial loss at the tips of villi, has been observed in other conditions that affect villus drainage or cause vascular changes in the villus core [4]. The mucosal congestion and hemoconcentration suggested by morphological studies has been conﬁrmed by simultaneous monitoring of mucosal perfusion, red cell volume and plasma volume. Ethanol signiﬁcantly increased mucosal blood ﬂow and red cell volume without an equivalent increase in plasma volume indicating hemoconcentration [12]. The mucosal microvascular stasis was accompanied by an intraluminal loss of plasma protein. This appears to be due to a transient increase in microvascular as well as epithelial permeability [4, 12]. This transient increase in permeability may be mediated by the effects of ethanol on the GI immune system. Effect of Ethanol on Small Intestinal Permeability Acute and chronic alcohol misuse impair the barrier function of the GI mucosa resulting in increased permeability and translocation of macromolecules [3, 4]. This is demonstrated by the observation that transient endotoxemia occurs following alcohol consumption by both healthy volunteers and chronic alcohol misusers with liver disease [3]. The GIT may be permeable in two directions; from the lumen to the wall or from the wall to the lumen. Ethanol increases both but the magnitude of the changes appears to be concentration- and species-dependent. Whether these effects on mucosal permeability are

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conﬁned to the upper small intestine or also occur in the colon remains uncertain [3]. Endotoxins are lipopolysaccharides on the surface of gram-negative bacteria. The GI immune system is one of the most important defenses against this antigen load. However, little is known about the effects of ethanol on the GI immune system. Effect of Ethanol on the Intestinal Immune System The immunomodulatory effects of alcohol misuse may cause inﬂammation which contributes to the development of organ injury, immunodeﬁciency and increased susceptibility to infections [13, 14]. In duodenal biopsies in alcoholic subjects abstaining for less than 5 days, the number of B-lymphocytes in the lamina propria was signiﬁcantly increased and the number of mononuclear macrophages was decreased by 50% [15]. These changes were not seen after 5–10 days. In mice the feeding of a liquid diet containing alcohol resulted in loss of lymphoid cells [16]. This reduction in the cellular immune response may increase the susceptibility to GI pathogens. Perfusion of segments of jejunum with 6% ethanol suggested that ethanol mediated some of the effects on the mucosa and GI permeability through promoting leukocyte inﬁltration and release of reactive oxygen species and histamine from mast cells [10, 17]. This is supported by the observation that this damage could be prevented by the administration of inhibitors of the adhesion of leukocytes and/or by free radical scavengers [17]. Bacterial Overgrowth of the Small Intestine Bacterial overgrowth in the small intestine has been demonstrated in patients with chronic alcohol abuse [18]. Alcohol misusers often have positive hydrogen breath tests for bacterial overgrowth in the small intestine [19]. The bacterial counts in the jejunum are elevated [20] with an increase in bacteria from the fecal ﬂora. The reason for the bacterial overgrowth in alcoholics is unclear. These bacteria may cause mucosal damage and contribute to the increased translocation of endotoxin [16]. ‘Endogenous’ ethanol is thought to be produced by the microbial fermentation of carbohydrates within the GIT [21]. Ethanol may thereby be present in the body even in the absence of alcohol intake. However, compared to the BEC produced by orally consumed ethanol (table 1), the BEC in sober people which may reach 0.39 8 0.45 g/ml [22] is very low. Thus, endogenous ethanol production will not be accepted by the police as an excuse for driving ‘over the limit’.

Rajendram /Preedy

Ethanol and Intestinal Absorption Absorption of nutrients from the lumen of the GIT occurs in 3 stages: (1) transport across the BBM; (2) passage across the enterocyte, and (3) transport out of the enterocyte across the basolateral membrane. Different mechanisms are involved at each stage for each nutrient and may be active or passive (diffusion). Ethanol reduces the effective surface area available for absorption and inhibits each of these processes. However, there is considerable functional reserve within the small intestine. Thus a partial inhibition of nutrient absorption in the proximal small intestine may be compensated by uptake in the distal small intestine. Effects of Ethanol on the Absorption of Macronutrients The absorption of carbohydrates, proteins and lipids has been studied in alcoholics without confounding disorders such as hepatic or pancreatic insufﬁciency [23]. Duodenal absorption was lower in alcoholics than agematched controls. However, there was no difference in jejunal absorption. This may reﬂect the greater alcoholinduced injury in the duodenum [23]. Measurement of the absorption of the monosaccharide -xylose can be used clinically to detect malabsorption. Several studies have shown malabsorption of xylose in alcoholics without liver disease. The proportion of alcoholics who manifest xylose malabsorption varied between studies but may be up to 75% [5]. Although chronic ethanol misuse does not seem to affect the absorption of glucose [10], acute alcohol inhibits both the active and the passive transport of glucose in vivo [24]. Ethanol concentrations over 2% also inhibit the absorption of amino acids, lipids, vitamins and trace elements [25]. However, this inhibition does not appear to be sustained by chronic ethanol administration which did not affect the absorption of L-leucine in rats fed a nutritious diet [26]. Effects of Ethanol on the Absorption of Micronutrients Ethanol inhibits the active transport of low concentrations of folate; however, it has no effect on the passive absorption at higher concentrations of folate. Folate deﬁciency, often observed in alcohol misuse [25, 27], is primarily due to malnutrition. Chronic alcohol consumption also leads to malabsorption of vitamin B12 which may be due to malabsorption of the vitamin in the terminal ileum [28]. However, few

Effect of Alcohol Consumption on the Gut

alcoholics have clinical evidence of B12 deﬁciency [27, 28]. Acute alcohol ingestion leads to an inhibition of thiamine absorption in healthy volunteers and in alcoholics [25]. Alcohol inhibits the sodium-dependent active transport of thiamine to the intestinal mucosa. However, at higher concentrations of thiamine, absorption is due to passive diffusion and is not affected by ethanol. Malabsorption of thiamine is reversible within weeks of abstinence [25]. Alcohol does not directly affect the absorption of the fat-soluble vitamins A, D, E and K. However, cholestasis due to alcoholic hepatitis and cirrhosis, pancreatitis and maldigestion can cause deﬁciencies of these vitamins [3, 5]. Decreased calcium absorption only occurs in the presence of alcoholic liver disease since this decrease in calcium absorption is due to a decreased concentration of 5-hydroxy-vitamin D due to a decreased activation in the liver. Iron stores are often increased in alcoholics [29]. However, the effects of alcohol on iron absorption remain unclear. An increase in the non-carrier-mediated paracellular absorption of iron may contribute to the iron overload in alcoholics [29]. This is particularly relevant for alcoholic beverages rich in iron such as Guinness. Following absorption, some nutrients are metabolized within the GIT. Ethanol affects this in several ways. Effects of Ethanol on Intestinal Metabolism Alcohol affects the metabolism of carbohydrates and lipids in the BBM of the small intestinal mucosa. Chronic alcohol intake damages the tips of the villi where lactase and sucrase are located. The activities of both enzymes are reduced which may exacerbate lactose intolerance [3, 7]. However, as villi regenerate rapidly, the activities of lactase and sucrase activity return to normal within weeks of abstinence. Intestinal triglyceride and cholesterol synthesis are both enhanced by acute and chronic alcohol administration [7]. The activities of enzymes responsible for fatty acid esteriﬁcation are also increased. Alcohol increases the secretion of triglycerides, cholesterol and phospholipids and transport proteins into lymph as well as lymphatic ﬂow [7]. These effects of ethanol may contribute to the development of alcoholic fatty liver [7]. Chronic alcohol consumption in man has been reported to increase the secretion of water and electrolytes in the jejunum and colon. This effect is enhanced by folate deﬁciency. The mechanism for this increased secretion of

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217

sodium and water is an increase in cyclic AMP due to an enhancement of mucosal adenylate cyclase activity [7, 25]. Alcohol also affects prostaglandin and leukotriene metabolism in the small intestinal mucosa. Prostaglandin E2, an important mucosal protective factor, is initially increased after alcohol administration, but after several weeks of alcohol exposure a reduction occurs [7]. This may increase the risk of GIT ulceration. It is also thought that alcohol may increase the production of 5-lipoxygenase products [7]. In addition, animal studies have shown that acute and chronic alcohol intake can signiﬁcantly inhibit protein synthesis in the mucosa cells as well as the contractile proteins of the smooth muscle [30]. This may, in part, explain the effects of alcohol on the motility of the GIT. Ethanol-Induced Changes in Small Intestinal Motility Food is retained for further digestion in the jejunum by impeding wave motility and propelled through the intestine by propulsive wave motility. Acute alcohol reduces impeding wave motility and increases propulsive wave motility [31]. This may result in reduced transit time to the colon and diarrhea, but there was no difference between chronic alcoholics or healthy volunteers [31]. The mechanism of these effects of ethanol are not well understood but are thought to be due to the direct and indirect effects of ethanol on the muscle and nerves of the GIT. Chronic alcohol misuse may either reduce or prolong small intestinal transit [31]. This effect of ethanol is not seen in all subjects and reverses with abstinence. Both abnormalities could contribute to diarrhea as shortened transit reduces absorption whilst prolonged transit predisposes to bacterial overgrowth [31].

Large Intestine

After oral intake, the majority of ingested ethanol is absorbed within the small intestine (table 1) [2]. The concentration of ethanol in the colon is relatively low and is mainly derived from the blood. Apart from the association of ethanol and malignancy (see Seitz et al: Alcohol consumption and cancer of the gastrointestinal tract, pp 297–303), the effect of ethanol on the colon has received little attention. One of the most important functions of the colon is to salvage water and electrolytes. This is indirectly assisted

218

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by a symbiotic relationship with the intracolonic luminal microﬂora which hydrolyze malabsorbed macronutrients [32]. These are then absorbed across the colonic mucosa, accompanied by water and electrolytes. Bacteriocolonic Pathway of Ethanol Metabolism Within the colon some ethanol is oxidized by bacterial alcohol dehydrogenase to acetaldehyde [33]. Acetaldehyde is then oxidized either by colonic mucosal or bacterial aldehyde dehydrogenase to acetate. Acetaldehyde may also be absorbed to the portal vein and metabolized in the liver. Due to the low aldehyde dehydrogenase activity of the colonic mucosa, acetaldehyde accumulates in the colon and may contribute to the pathogenesis of alcohol-induced diarrhea and colon cancer [33]. Effect of Ethanol on Colorectal Motility Data on the effect of chronic ethanol on colonic motility are sparse. Intravenous ethanol increases the colonic tone and motility in dogs and reduces the transit time of a bolus [3, 34]. A rapid rectosigmoid transit in alcoholics has also been observed [31, 34]. Total and segmental colonic transit times were estimated in 20 alcoholics for 4 days and again 10 days after admission to a detoxiﬁcation unit [31]. Colonic transit times in withdrawing alcoholics were similar to controls. These data suggest that a reversible increase in rectosigmoid transit time in alcoholics could contribute to transient diarrhea in alcoholics. Effects of Alcohol on Colonic Morphology The morphology of the rectum is altered by chronic alcohol misuse. Rectal biopsies often show crypt destruction and inﬂammation. These changes return to normal after 3 weeks of abstinence [35]. Chronic alcohol consumption increased the crypt cell production rate and resulted in extension of the proliferative compartment of the crypt in rodents. This was associated with a decrease in the functional compartment [36]. Also, chronic alcoholics had an increased proliferation in their crypts with an extension of their proliferative compartments. Abnormal cellular proliferation is the hallmark of malignant neoplasia (see Seitz et al: Alcohol consumption and cancer of the gastrointestinal tract, pp 297–303).

Clinical Manifestations

Despite the signiﬁcant functional reserve of the GIT, the effects of alcohol on GI mucosal morphology and function often manifest clinically. Although high concen-

Rajendram /Preedy

Sarcoplasmic fraction

25

Total protein (mg)

p < 0.01

NS

20 15

p < 0.05

10

p < 0.01

p < 0.05

5 0 Control Ethanol

Fig. 2. The effect of ethanol administration for 6 weeks on subcellular protein composition in the small and large intestine of rats. Data are presented as means. NS = p 1 0.05; SM = seromuscular layer. Adapted from Marway and Preedy [38].

Total protein (mg)

12

Myofibrillar fraction

NS

10 8 6

p < 0.05

p < 0.05

4

p < 0.01

p < 0.05

Jejunum SM

Ileum SM

2 0 Duodenum SM

Jejunum whole

Rectum and colon SM

trations of ethanol administered acutely do cause GI upset, most of the clinically relevant changes occur with chronic alcohol consumption. However, because of its rapid epithelial turnover, the GIT mucosa usually returns to normal soon after abstinence [5]. Administration of a single beverage with a high ethanol concentration may cause duodenal erythema and epithelial bleeding [3, 4, 9]. Upper GIT endoscopy often reveals severe ulceration of the mucosa of the duodenum and upper jejunum of ethanol misusers [3, 4, 9]. This mucosal damage could affect the digestion and absorption of macro- and micronutrients. Fecal fat excretion is increased in alcoholics. The pathogenesis of this is multifactorial but malabsorption of lipids is particularly important in alcoholics without liver disease [7]. However, pancreatic dysfunction, bacterial overgrowth and changes in bile acid metabolism may also be involved [7]. Malabsorption of lipids affects the absorption of fat-soluble vitamins. The reduction of vitamin D and calcium absorption may contribute to the development of alcoholic osteopathy [7]. The reduced absorption of amino acids in alcoholics may exacerbate the malnutrition which often develops [3, 5, 7, 23, 25]. Malabsorption of vitamins can have devastating consequences for alcohol misusers. For example thiamine deﬁciency may lead to Wernicke’s encephalopathy and Korsakoff’s psychosis, whilst vitamin

B12 deﬁciency may cause peripheral neuropathy or subacute and combined degeneration of the spinal cord [7, 25]. Bacterial overgrowth and increased mucosal permeability results in increased uptake of macromolecular bacterial toxins such as endotoxin from the intestinal lumen which can enter portal blood, leading to endotoxemia and activation of hepatic macrophages [7, 13, 14, 18–20]. The stimulation of these cells results in the release of mediators of inﬂammation (cytokines) and reactive oxygen species. This endotoxemia has been implicated in the pathogenesis of hepatic cirrhosis [7, 20]. Chronic alcohol misuse or a single dose of ethanol of 140 g often results in diarrhea [3, 4, 7]. This is mainly due to reduced absorption and increased secretion of sodium and water. However, disturbed GI motility, malabsorption and reduced lactase activity also contribute [3, 4, 7]. Reduced lactase activity, partly due to microvilli blunting and loss of functional enterocytes, leads to lactose intolerance. Diarrhea and gas production occurs shortly after ingestion of dairy products. The management of these problems is superﬁcially very simple as the effects of ethanol on the GIT usually resolve within weeks of abstinence.

Effect of Alcohol Consumption on the Gut

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219

Fig. 3. The effects of acute ethanol dosage

on contractile protein synthesis in the rat gastrointestinal tract. Data are presented as means. NS = p 1 0.05. Adapted from Marway et al. [39].

Rate of protein synthesis (k s ; %/day)

60 p < 0.001

50

p < 0.05

40

NS

30

20

10

0 Duodenum

The pathogenesis of the effects of ethanol on the GIT have been extensively investigated but remain unclear. Some of the effects of ethanol may be explained by disruption of protein metabolism [30]. Protein metabolism is a dynamic process, involving both protein synthesis and degradation. Alterations in one or both of these processes can affect tissue protein content. The rate of protein synthesis varies throughout the GIT (ﬁg. 2, 3). The rate of protein synthesis is 2–3 times faster in the GI mucosa than the seromuscular layer [30, 37, 38]. This is probably because the luminal mucosal cells have a high rate of turnover. The rate of protein synthesis is higher in the small intestine than any other region of the GIT [30, 38, 39]. The synthetic rates of various protein fractions also differ, for example, the rate of protein synthesis of the sarcoplasmic (i.e. cytoplasmic) fraction is higher than the myoﬁbrillar fraction [30]. Both acute and chronic ethanol administration results in a reduction of protein synthesis in the mucosal and seromuscular layers of the small intestine (ﬁg. 2, 3) [30, 38, 39]. However, protein synthesis in the colon is relatively unaffected [30, 38, 39]. Thus ethanol selectively affects different parts of the GIT. The understanding of protein synthesis within the small intestine has been greatly increased by studies of the effects of alcohol. However, the mechanisms of the ethanol-induced toxicity to GIT protein synthesis remain unclear. The effects of ethanol on the endocrine system may contribute [30]. Attention has also focused on the

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NS

NS

Pathogenic Mechanisms

220

Control Ethanol

p < 0.05

Jejunum

Ileum

Cecum

Colon

Rectum

role of free radicals and oxidative stress in the effects of ethanol on the GIT [30]. The role of nitric oxide in small intestinal protein synthesis has recently been investigated [37]. Administration of nitric oxide synthase inhibitors reduced the rate of jejunal protein synthesis in control animals and also increased the sensitivity of jejunal protein synthesis to acute ethanol in vivo [37]. This suggests that production of nitric oxide is not involved in the ethanol-induced reduction of protein synthesis in the jejunum. There is a need for more research into the mechanisms underlying the effects of ethanol on the GIT.

Future Developments

Investigation of the pathogenesis of the effects of ethanol has traditionally been hypothesis-driven. Importantly, it has been elucidated that some processes are not affected by either acute or chronic alcohol exposure. Whilst hypothesis-driven research is clearly important, the application of holistic, or ‘omic’, technologies could rapidly highlight signiﬁcant pathways, processes or products. In particular, genomics, proteomics and metabolomics could identify thousands of molecular and cellular targets involved in the effects of ethanol on the GIT.

Rajendram /Preedy

References 1 Kalant H: Effects of food and body composition on blood alcohol levels; in Preedy VR, Watson RR (eds): Comprehensive Handbook of Alcohol Related Pathology. London, Academic Press, 2004, pp 87–102. 2 Halsted CH, Robles EA, Mezey E: Distribution of ethanol in the human gastrointestinal tract. Am J Clin Nutr 1973;26:831–834. 3 Bode C, Bode JC: Effect of alcohol consumption on the gut. Best Pract Res Clin Gastroenterol 2003;17:575–592. 4 Beck T: Small bowel injury by ethanol; in Preedy VR, Watson RR (eds): Alcohol and the Gastrointestinal Tract. Boca Raton, CRC Press, 1996, pp 163–202. 5 Thompson AD, Heap LC, Ward RJ: Alcohol induced malabsorption in the gastrointestinal tract; in Preedy VR, Watson RR (eds): Alcohol and the Gastrointestinal Tract. Boca Raton, CRC Press, 1996, pp 203–218. 6 Caballeria J, Frezza M, Hernadez-Munoz R, Dipadova C, Korsten MA, Baraona E, Lieber CS: Gastric origin of the ﬁrst pass metabolism of ethanol in humans: effect of gastrectomy. Gastroenterology 1989;97:1205–1209. 7 Ergerer G, Stikel F, Seitz HK: Alcohol and the gastrointestinal tract; in Preedy VR, Watson RR (eds): Reviews in Food and Nutrition Toxicity. London, Taylor & Francis, 2005, vol 2, pp 559–572. 8 Seitz HK, Velasquez D, Waldherr R, Veith S, Czygan P, Weber E, Deutsch-Diescher OG, Kommerell B: Duodenal gamma-glutamyltransferase activity in human biopsies: effect of chronic ethanol consumption and duodenal morphology. Eur J Clin Invest 1985; 15: 192– 196. 9 Mazzanti R, Jenkins WJ: Effect of chronic ethanol ingestion on enterocyte turnover in rat small intestine. Gut 1987;28:52–55. 10 Beck IT, Dinda PK: Acute exposure of small intestine to ethanol: effects on morphology and function. Dig Dis Sci 1981;26:817–838. 11 Buell MG, Beck IT: Effect of ethanol on jejunal regional blood ﬂow in the rabbit. Gastroenterology 1983;84:81–89. 12 Buell MG, Beck IT: Ethanol-induced mucosal microvascular stasis and enhanced plasma protein loss in the dog jejunum. Gastroenterology 1984;86:413–420. 13 MacGregor RR: Alcohol and immune defence. JAMA 1986;256:1474–1479. 14 MacGregor RR, Louria DB: Alcohol and infection. Curr Clin Top Infect Dis 1997; 17: 291– 315. 15 Maier A, Bode C, Fritz P, Bode JC: Effects of chronic ethanol abuse on duodenal mononuclear cells in man. Dig Dis Sci 1999; 44: 691– 696.

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16 Sibley D, Jerrells TR: Alcohol consumption by C57BL/6 mice is associated with depletion of the gut associated lymphoid tissues and altered resistance to oral infections with Salmonella typhimurium. J Infect Dis 2000; 182: 482– 489. 17 Dinda PK, Kossev P, Beck IT, Buell MG: Role of xanthine oxidase-derived oxidants and leukocytes in ethanol-induced jejunal mucosal injury. Dig Dis Sci 1996;41:2461–2470. 18 Hauge T, Persson J, Danielsson D: Mucosal bacterial growth in the upper gastrointestinal tract in alcoholics (heavy drinkers). Digestion 1997;58:591–595. 19 Morencos FC, de las Heras Castano G, Martin Ramos L, Lopez Arias MJ, Ledesma F, Pons Romero F: Small bowel bacterial overgrowth in patients with alcoholic cirrhosis. Dig Dis Sci 1995;40:1252–1256. 20 Bode C, Schaefer K, Bode JC: The role of gutderived bacterial toxins (endotoxins) for the development of endotoxins in man; in Blum HC, Bode C, Bode JC, Sartor RB (eds): Gut and the Liver. Falk Symposium 100. Dordrecht, Kluwer, 1998, pp 281–298. 21 Blomstrand R: Observations of the formation of ethanol in the intestinal tract in man. Life Sci 1971;10:575–582. 22 Jones AW, Mardh G, Anggard E: Determination of endogenous ethanol in blood and breath by gas chromatography – mass spectrometry. Pharmacol Biochem Behav 1983; 18(suppl 1): 267–272. 23 Pfeiffer A, Schmidt T, Vidon N, Pehl C, Kaess H: Absorption of a nutrient solution in chronic alcoholics without nutrient deﬁciencies and liver cirrhosis. Scand J Gastroenterol 1992;27: 1023–1030. 24 Seitz HK, Homann N: Effect of alcohol on the orogastrointestinal tract, the pancreas and the liver; in Heather N, Peters TJ, Stockwell T (eds): International Handbook of Alcohol Dependence and Problems. Chichester, Wiley, 2001, pp 149–167. 25 Seitz HK, Suter PM: Ethanol toxicity and nutritional status; in Kotsouis FM, Mackey M (eds): Nutritional Toxicology, ed 2. London, Taylor & Francis, 2002, pp 122–154. 26 Martines D, Morris AI, Billington D: The effect of chronic ethanol intake on leucine absorption from the rat small intestine. Alcohol Alcohol 1989;24:525–531. 27 Halsted CH, Keen CL: Alcoholism and micronutrient metabolism and deﬁciencies. Eur J Gastroenterol Hepatol 1990;6:399–405.

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28 Lindenbaum J: Folate and vitamin B12 deﬁciencies in alcoholism. Semin Hepatol 1980; 17:119–129. 29 Duane P, Raja KB, Simpson RJ, Peters TJ: Intestinal iron absorption in chronic alcoholics. Alcohol Alcohol 1992;27:539–544. 30 Marway JS, Bonner A, Preedy VR, Peters TJ: Protein synthesis in the gastrointestinal tract and its modiﬁcation by ethanol; in Preedy VR, Watson RR (eds): Alcohol and the Gastrointestinal Tract. Boca Raton, CRC Press, 1996, pp 255–272. 31 Keshavarzian A, Fields JZ: Gastro-intestinal motility disorders induced by ethanol; in Preedy VR, Watson RR (eds): Alcohol and the Gastrointestinal Tract. Boca Raton, CRC Press, 1996, pp 235–254. 32 Grimble GK: The physiology of digestion, absorption and metabolism in the human intestine; in Preedy VR, Watson RR (eds): Alcohol and the Gastrointestinal Tract. Boca Raton, CRC Press, 1996, pp 79–110. 33 Salaspuro M: Bacteriocolonic pathway for ethanol oxidation: characteristics and implications. Ann Med 1996;28:195–200. 34 Bouchoucha M, Nalpas B, Berger M, Cugnenc PH, Barbier JP: Recovery from disturbed colonic transit time after alcohol withdrawal. Dis Colon Rectum 1991;34:111–114. 35 Simanowski UA, Seitz HK, Baier B, Kommerell B, Schmidt-Gayk H, Wright NA: Chronic ethanol consumption selectively stimulates rectal cell proliferation in the rat. Gut 1986;27: 278–282. 36 Simanowski UA, Suter P, Russell RM, Heller M, Waldherr R, Ward R, Peters TJ, Smith D, Seitz HK: Enhancement of ethanol induced rectal mucosal hyper regeneration with age in F344 rats. Gut 1994;35:1102–1106. 37 Rajendram R, Marway JS, Mantle D, Peters TJ, Preedy VR: Skeletal muscle and jejunal protein synthesis in normal and ethanol-treated rats: the effect of the nitric oxide synthase inhibitors, L-omega-nitro-L-arginine methyl ester and N(G)-nitro-L-arginine in vivo. Metabolism 2003;52:397–401. 38 Marway JS, Preedy VR: Contractile and noncontractile proteins and nucleic acids in the stomach, whole jejunum and seromuscular layers of the duodenum, jejunum, ileum and large intestine in response to chronic ethanol feeding. Alcohol Alcohol 1991;26:549–557. 39 Marway JS, Siddiq T, Gibbs P, Edwards P, Preedy VR: Contractile and non-contractile protein synthesis in the small and large intestine and their response to acute ethanol dosage. Biochem Soc Trans 1994;22:194S.

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Europe demonstrated an incidence of 8.2 cases/year/ 100,000 individuals, and an overall prevalence of 27.4 cases within a population of 100,000 individuals [5]. Several autopsy studies investigated the prevalence of chronic pancreatitis in patients with chronic alcoholism. Pitchumoni et al. [9] investigated the pancreas of 101 patients with chronic alcohol abuse who had never experienced acute pancreatitis during their lives. Diffuse ﬁbrosis was found in 47% of the alcoholics [9]. In another study of 99 alcoholic patients who died from alcohol-related disease, 18% presented with perilobular sclerosis as evidence of alcohol-induced pancreatic damage [10]. These ﬁndings suggest that changes in chronic pancreatitis may frequently develop in alcoholic individuals, but that the pancreatic damage most often remains asymptomatic.

Alcohol Consumption and Pancreatitis

Most patients with alcoholic chronic pancreatitis consumed large amounts of alcohol before the ﬁrst clinical onset of the disease with intakes ranging between 80 and 1500 g/day for several years [2, 4, 6, 8, 17]. The interval between the start of continuous alcohol abuse and the typical clinical manifestation of alcohol-induced chronic pancreatitis usually requires between 13 and 21 years [4, 6]. Based on clinical observations, an international conference on alcoholic chronic pancreatitis agreed to deﬁne alcoholic chronic pancreatitis as chronic pancreatitis which occurs after a daily intake of alcohol of 680 g/day for several years [18]. However, there appears to be no precise threshold of toxicity below which alcoholic pancreatitis does not occur. Although the risk of developing alcoholic chronic pancreatitis increases logarithmically with higher amounts of alcohol consumption [4], an increased risk of developing the disease has been reported in patients with moderate amounts of alcohol consumption such as 20 g/day [4]. Thus, a simple dose-related injury model for the development of the disease must be rejected [2, 4]. In general, the relationship between alcohol consumption and chronic pancreatitis is weak compared with the association between alcohol intake and liver cirrhosis and other common alcohol-related conditions [13]. The speciﬁc type of alcoholic beverage consumed by patients with alcoholic chronic pancreatitis represents another issue which has been proposed to result in pancreatic damage. Alcoholic chronic pancreatitis is observed in patients with a dominant consumption of beer, wine, hard liquor and other alcoholic beverages [19–21]. In addition, the disease occurs in patients with different kinds of drinking patterns [19–21]. Therefore, the speciﬁc type of alcoholic beverage or the type of drinking pattern do not appear to play a dominant role in the development of the disease.

The epidemiological data suggest that heavy alcohol consumption causes pancreatitis in humans. However, a strong relationship between alcohol consumption and chronic pancreatitis does not exist. Several lines of evidence rather suggest that alcohol alone cannot explain pancreatic inﬂammation. First, it remains unclear why only about 10% of heavy alcohol drinkers ever develop clinically recognized pancreatic inﬂammation [11]. Second, the susceptibility of various organs to alcohol may differ. Some alcoholics develop alcoholic chronic pancreatitis while others develop liver disease, but only few patients present with both conditions requiring clinical care [12]. Although some degree of pancreatic injury and liver ﬁbrosis often occurs in the same alcoholic patients [13], the relationship between alcohol consumption and the resulting end organ damage appears unpredictable. Third, the progression and clinical course of pancreatic disease demonstrates a marked variability [14]. One third of alcoholic patients with recurrent acute pancreatitis did not progress towards chronic calcifying pancreatitis during an observation period of 11.7 8 5.8 years [15]. Fourth, differences in racial susceptibility may exist since black patients are 2–3 times more likely to be hospitalized for pancreatitis than white patients [16]. These observations demonstrate a marked heterogeneity in susceptibility to chronic alcoholic pancreatitis. Therefore, it may be suggested that alcohol rather represents a cofactor in the development of alcoholic pancreatitis in susceptible humans. The other yet to be determined cofactors could be environmental or genetic.

Patients with alcoholic chronic pancreatitis present with a broad spectrum of clinical features. The majority of patients with alcoholic chronic pancreatitis are diagnosed between 35 and 40 years of age [22]. Usually, the early phase of the disease is characterized by recurrent painful attacks of acute pancreatitis. These attacks are indistinguishable from other etiologic forms of the disease such as biliary pancreatitis. This initial phase may last for several years and is usually followed by the late

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phase of the disease which is characterized by the development of chronic pain, pancreatic calciﬁcations, and exocrine and endocrine insufﬁciency. Abdominal pain represents the leading symptom in the majority of patients and remains the most serious clinical problem in chronic pancreatitis. Abdominal pain typically increases after a meal, limits the food consumption and contributes to weight loss and malnutrition. Chronic pain results in a reduction in quality of life and loss of social functioning. Two clinically distinct pain patterns, the A- and B-type, appear in patients with alcoholic pancreatitis [14]. The A-type is characterized by short relapsing pain episodes separated by pain-free episodes lasting up to several years while the B-type is characterized by prolonged periods of either persistent pain or clusters of recurrent severe pain. A-type pain links recurrent attacks of acute pancreatitis with the initiation of alcoholic chronic pancreatitis [14, 23]. However, up to 67% of patients with alcoholic chronic pancreatitis experience periods of protracted pain severe enough to warrant surgical intervention already in early stages of the disease [14]. Of note, not all patients with chronic pancreatitis will suffer acute episodes of pancreatitis. The course of pain in chronic pancreatitis remains unpredictable in individual cases. In one series, more than 80% of patients achieved lasting pain relief within 10 years from onset of the disease [14]. Moreover, this pain relief was closely related with the development of marked exocrine insufﬁciency [14, 24]. However, another study did not conﬁrm these observations of a ‘pancreatic burnout’ [25]. This study reported pain relief in only 50% of 335 patients at the end of a median observation period of 9.8 years [25]. About 10% of patients with alcoholic chronic pancreatitis are diagnosed with exocrine or endocrine insufﬁciency without prior abdominal pain [7, 26]. Steatorrhea as sign of exocrine insufﬁciency is observed in advanced stages of the disease since the pancreas possesses a large exocrine reserve. DiMagno et al. [27] demonstrated that steatorrhea does not occur until pancreatic lipase secretion is reduced to less than 10% of normal. Patients with exocrine insufﬁciency typically present with weight loss since the maldigestion of fat, protein and carbohydrates results in malabsorption. The stool typically appears bulky, foul-smelling and fatty, and undigested portions of previously consumed nutrition may be found. In addition, vitamin deﬁciency may occur. The interval between onset of the disease and the occurrence of persistent exocrine insufﬁciency and calciﬁcations averages 4.8 8 5.5 years in alcoholic chronic pancreatitis [15]. Another study reported a median time of

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13.1 years to pancreatic exocrine insufﬁciency after onset of the disease, whereas endocrine insufﬁciency developed after a median time of 19.8 years [7]. Diabetic microangiopathic complications are noted in patients with chronic pancreatitis [28]. Data regarding the progression of pancreatic insufﬁciency are conﬂicting. Several investigations did not show progressive deterioration or revealed even slight improvements in pancreatic insufﬁciency over time [7, 25]. In contrast, other reports show progressive deterioration of pancreatic function during a median follow-up of 10.4 years in patients with alcoholic chronic pancreatitis [23]. The reasons for these differences are not clariﬁed but may result from differences in study designs or sensitivities of the pancreatic function tests used in the investigations. Although the progression towards pancreatic insufﬁciency is not completely halted by cessation of alcohol abuse, abstinence may diminish the progression to exocrine and endocrine insufﬁciency [29]. In addition, a decrease in pain or a decrease in the frequency of episodes of acute pancreatitis has been shown in patients who stop drinking alcohol [30]. The relationship between acute and chronic alcoholic pancreatitis remains controversial [31]. Studies in patients with an initial episode of acute pancreatitis revealed that these patients already presented histological changes of chronic pancreatitis [9, 10]. However, several long-term clinical studies [15, 23], pathologic studies [32, 33], investigations in patients with hereditary pancreatitis [34, 35], and recent experimental studies [36] provide strong evidence that recurrent attacks of acute pancreatitis can result in chronic pancreatitis. Indeed, Renner et al. [37] studied 405 patients who died of acute pancreatitis. In 247 patients chronic alcohol abuse was documented. Signs of chronic pancreatitis were only found in about half of these individuals. Thus, the concept that acute pancreatitis represents the ﬁrst recognition of chronic pancreatitis appears to be valid in about half of the 247 alcoholic patients who died of acute pancreatitis, but not in the other half of patients without signs of chronic pancreatic damage [37]. In summary, the combination of alcohol abuse with further alcohol-related problems, the poor socioeconomic status and the development of abdominal pain with exocrine and endocrine insufﬁciency represent a clinical challenge that remains difﬁcult to treat in many patients. The mortality rate in patients with alcoholic chronic pancreatitis is approximately one third higher than that in an age- and sex-matched general population [38]. About 50% of patients with the disease die within 20 years after onset

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Fig. 1. Pancreas with typical morphological changes of chronic pancreatitis such as ﬁbrosis and calciﬁcations. Kindly provided by R. Hildenbrand and U. Bleyl, Department of Pathology, University Hospital of Heidelberg at Mannheim.

Fig. 2. Histology of chronic pancreatitis. Normal pancreatic acinar cells are lost and replaced by extensive ﬁbrosis. Kindly provided by R. Hildenbrand and U. Bleyl, Department of Pathology, University Hospital of Heidelberg at Mannheim.

with a median age of 54 years [15]. However, mortality is not related to chronic pancreatitis and its complications in 80% of the patients [7, 15]. The most common causes of death remain heavy smoking, malignancies, cardiovascular diseases and ongoing alcohol abuse with associated complications [26]. Thus, the prognosis of alcoholic chronic pancreatitis is relatively poor, and the disease needs the attention of both clinicians and social care workers.

become more abnormal with stricture formation and dilatation. Furthermore, an increase in the diameter and number of intrapancreatic nerves, inﬁltration of nerves with inﬂammatory cells and damage to the perineural sheath are noted in pancreatic tissue [42]. Electron microscopy reveals lipid inclusions in the acinar cell cytoplasm, a decrease in zymogen granule number, dilatation of the endoplasmic reticulum and mitochondrial damage [43]. Based on the predominating structural features, descriptive terms such as ‘chronic pancreatitis with focal necrosis’, ‘chronic pancreatitis with segmental or diffuse ﬁbrosis’, ‘chronic pancreatitis with or without calculi’, or ‘obstructive chronic pancreatitis’ may be used [44]. Of note, most of the morphological changes of chronic pancreatitis have been reported in pancreatic tissue from autopsy studies or from tissue obtained during surgical interventions. Therefore, advanced forms of the disease may be over represented [38]. Typical changes that are usually found in patients with advanced forms of chronic pancreatitis are given in ﬁgures 1 and 2.

Pathology

Both alcoholic and non-alcoholic chronic pancreatitis result in indistinguishable pancreatic damage. In the early course of the disease, ﬁbrosis is found with inﬁltrating lymphocytes, plasma cells and macrophages [39]. The islet cells are usually not affected until very late during the course of the disease [40]. Within the pancreas, areas with signs of acute pancreatitis such as edema or focal tissue necrosis may be found [41]. Fat droplets have been described in the pancreatic acinar cell [38]. The full picture of chronic pancreatitis is characterized by a nodular, hard organ that is either enlarged or atrophic. The ﬁbrotic destruction of the organ progresses, and blockage of the pancreatic ducts with protein plugs is observed. However, ﬁbrosis may occur segmentally or nonsegmentally [32]. Cysts and pseudocysts are not uncommon [33, 41]. Characteristic calciﬁcations develop and the pancreatic ducts

Alcoholic Pancreatitis

Theories on the Origin of Alcoholic Pancreatitis

Clinical and experimental studies that try to reveal the early cellular and molecular events resulting in acute and chronic pancreatitis are hampered by several factors. The pancreas is inaccessible to examination due to the loca-

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Table 1. Major ﬁndings in animal models of acute and chronic ethanol administration on pancreatic morphology

Major ﬁndings with animal models of acute ethanol administration Ethanol administration (intragastrically, intraperitoneally, intravenously) with physiological stimulation (cholecystokinine, secretin) and obstruction of the pancreatic duct results in acute pancreatitis Ethanol administration enhances the vulnerability of the pancreas to develop acute pancreatitis and limits pancreatic regeneration from acute pancreatitis Ethanol administration selectively reduces pancreatic blood ﬂow and microcirculation Cigarette smoke enhances ethanol-induced pancreatic ischemia Ethanol administration increases free oxygen radical generation in the pancreas Ethanol metabolites directly damage the pancreas Major ﬁndings with animal models of chronic ethanol administration Dietary fat potentiates ethanol-induced pancreatic injury Ethanol administration increases free oxygen radical generation in the pancreas Ethanol administration increases pancreatic acinar cell expression and glandular content of digestive and lysosomal enzymes Ethanol administration decreases the number of muscarinic receptor sites Ethanol administration limits pancreatic regeneration after temporary obstruction of the pancreatic duct and further aggravates already induced pancreatic damage Ethanol administration sensitizes pancreatic acinar cells to endotoxin-induced injury Ethanol administration enhances the vulnerability of the pancreas to pancreatitis caused by cholecystokinine octapeptide Experimental studies have provided various insights into the mechanisms whereby alcohol damages the pancreas. It is likely that several mechanisms act together and increase the risk of developing alcoholic chronic pancreatitis [for review, see 45].

tion of the pancreas within the retroperitoneal space. Thus, determination of the extent of pancreatic damage during the course of acute pancreatitis relies on modern imaging techniques. The diagnosis of acute pancreatitis in humans is usually delayed beyond the initiating phase of the disease, and a clear distinction between the initiating events and the subsequent inﬂammatory responses is often impossible. The understanding of the disease mechanisms in chronic pancreatitis raises similar difﬁculties. The diagnosis of chronic pancreatitis early in the course of the disease is usually impossible due to difﬁculties in recognizing early morphological alterations of pancreatic structure and difﬁculties with pancreatic function tests. Histological conﬁrmation and staging of suspected disease are seldom done. The clinical investigation of the disease provided limited insights into the early molecular mechanisms of pancreatic inﬂammation. Although animal models representing the human disease have been extremely difﬁcult to develop, experimental studies provided major insights into the mechanisms of pancreatic damage through ethanol and its metabolites [45]. Recently, animal models have been developed that result in pancreatic ﬁbrosis and pancreatic damage similar to human chronic pancreatitis [36, 46]. In these models, chronic

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ethanol exposure was combined with the administration of repeated episodes of cerulein-induced experimental pancreatitis [36, 46]. Table 1 summarizes the major effects of acute and chronic alcohol administration on pancreatic morphology [45]. Alcohol consumption also results in changes in pancreatic exocrine secretion [47]. An overview on the effects of acute and chronic ethanol administration on pancreatic exocrine secretion in humans and animals is provided in table 2 [47]. In the past, several hypothetical concepts have been proposed explaining the early and late pathophysiological mechanisms of alcoholic chronic pancreatitis. These concepts depend on the etiology of the disease, the stage of the disease and the genetic or environmental characteristics of the patient. However, currently no generally accepted concept for the disease exists. The physician Chiari [48] challenged the notion that pancreatitis was an infectious disease and in 1896 proposed that ‘pancreatic autodigestion’ represents the underlying pathophysiological mechanism of the disease. Since then, several hypothetical concepts have been proposed to explain the pathophysiological mechanisms in chronic pancreatitis and the interaction with environmental factors such as alcohol consumption.

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Table 2. Major ﬁndings in studies on humans and ethanol-fed animals on pancreatic exocrine secretion

Acute ethanol administration Oral and intragastric ethanol administration increases pancreatic bicarbonate and protein secretion Intravenous ethanol administration reduces basal and hormonally stimulated pancreatic bicarbonate and protein secretion Non-alcoholic constituents of beer may increase pancreatic secretion Chronic ethanol administration In human alcoholics, basal pancreatic enzyme secretion is increased In human alcoholics, the viscosity of the pancreatic juice is enhanced In human alcoholics, the pancreatic juice contains a higher concentration of proteins In human alcoholics, pancreatic bicarbonate secretion is decreased In human alcoholics, an enhanced ratio of trypsinogen levels to pancreatic secretory trypsin inhibitor levels is present in the pancreatic juice In ethanol-fed animals, a diet rich in fat and protein increases the concentrations of enzymes in the pancreatic juice Acute and chronic ethanol administration result in changes in pancreatic exocrine secretion in humans and animals. Thus, changes in pancreatic exocrine secretion patterns may contribute to the development of pancreatic damage [for review, see 47].

Recurrent Acute Pancreatitis Hypothesis

In 1946, Comfort et al. [49] investigated chronic pancreatitis tissue and concluded that chronic pancreatitis in alcoholics might result from repeated episodes of acute pancreatitis. The concept that ‘recurrent acute pancreatitis’ leads to chronic pancreatitis was accepted for decades. However, the alternate hypothesis, that in alcoholics recurrent acute pancreatitis represents a manifestation of underlying chronic pancreatitis, and that recurrent acute pancreatitis does not progress to chronic pancreatitis [50], became the dominant view in the 1960s through the early 1990s.

ductal obstruction’ in the pathogenesis of chronic pancreatitis. The hypothesis suggested that chronic alcohol consumption leads to a decrease in bicarbonate concentration and the volume of pancreatic secretion, and was associated with precipitation of protein and calcium crystals within the duct that were responsible for duct obstruction. The evidence supporting this hypothesis focused on a pancreatic stone protein, termed lithostathine, that was believed to stabilize pancreatic juice and inhibit calcite crystal formation [52]. Thus, alcoholic chronic pancreatitis was believed to represent a state of diminished ductal ﬂow, unstable pancreatic juice biophysics, calcium and protein precipitation, duct obstruction, pancreatic inﬂammation and ﬁnally ﬁbrosis. Although the predicted biophysics of lithostathine with respect to enhanced stabilization of calcium carbonate could not be demonstrated [53], duct plugging may play an important role in the pathogenesis of chronic pancreatitis. Indeed, the pathological evidence for duct plugging in pancreatic damage of cystic ﬁbrosis is unquestioned, and it is likely that the development of duct plugs within the course of alcoholic chronic pancreatitis contributes to and accelerates the progression of this disease.

Intraductal Obstruction Hypothesis Based on the morphological features of pancreatic specimens, experts at the 1963 Marseille meeting agreed that acute pancreatitis could not be the cause of chronic pancreatitis [50]. Arguments in support of this view included the observation that the average age of patients presenting with acute pancreatitis was 13 years older than the age of patients with chronic pancreatitis at their ﬁrst attack. Moreover, other factors such as gallstones, alcoholism and sex ratio were different in the two groups. Therefore, it was concluded that acute and chronic pancreatitis represent different diseases [50]. It was suggested that the primary lesion responsible for the development of chronic pancreatitis resided within the pancreatic duct. Sarles et al. [51] proposed the concept of ‘primary intra-

Toxic-Metabolic Hypothesis Bordalo et al. [54] suggested that alcoholic chronic pancreatitis was associated with the toxic-metabolic effects of alcohol. The primary toxic-metabolic hypothesis of alcoholic pancreatitis predicted that alcohol and its

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metabolites would change the intracellular lipid metabolism leading to fatty degeneration of the pancreatic acinar cells. Subsequently, pancreatic ﬁbrosis and secretory changes, as seen by Sarles et al. [51], would develop secondary to morphological alterations [54]. Indeed, the generation of these toxic products within the pancreas continues to be demonstrated [55, 56]. Oxidative Stress Hypothesis Braganza [57] postulated the concept of oxidative stress as the pathophysiological mechanism of recurrent acute pancreatitis that eventually leads to chronic pancreatitis. Oxygen-free radicals may challenge the protective antioxidant mechanisms, may damage the pancreatic acinar cell membranes, and were predicted to initiate acute pancreatitis. It was suggested that ongoing oxidative stress subsequently leads to chronic pancreatitis [58, 59]. However, oxidative stress is clearly present in the pancreas of rats chronically fed alcohol, but these animals do not develop chronic pancreatitis [59]. Necrosis-Fibrosis Hypothesis Klöppel and Maillet [32] revisited the hypothesis of Comfort et al. [49] and suggested that chronic pancreatitis is the result of repeated attacks of acute pancreatitis. These recurrent episodes of acute pancreatitis might lead to acinar cell necrosis and fat necrosis. This concept was named the necrosis-ﬁbrosis hypothesis and requires repeated episodes of acute pancreatitis to induce areas of focal necrosis and healing that eventually lead to pancreatic ﬁbrosis [32]. Pancreatic pseudocysts are common in both acute and chronic pancreatitis and present identical histological features. This observation suggested that chronic pancreatitis represents a late stage of relapsing acute pancreatitis [33]. Both acute and chronic pancreatitis are strongly associated with excessive alcohol consumption. The results from a long-term study with patients with chronic pancreatitis [15] and insights gained from studies in hereditary pancreatitis [34, 35] further support this concept. Arguments against this hypothesis include the observation that experimental acute pancreatitis and biliary pancreatitis almost never progress to chronic pancreatitis. In addition, some patients with alcoholic chronic pancreatitis demonstrate little evidence of acute pancreatitis or pancreatic necrosis. A prospective investigation of 144 patients with alcohol-induced pancreatitis revealed a subgroup of patients who did not show morphological features of chronic pancreatitis even though repeated episodes of acute pancreatitis were documented [60]. Furthermore, no histological evidence of

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chronic pancreatitis was detected in 5 of 7 pancreatic specimens [60]. Thus, although the necrosis-ﬁbrosis concept represents a logical approach to the pathophysiology of chronic pancreatitis in many cases, some skepticism remains. Sentinel Acute Pancreatitis Event Hypothesis Recent advances in pancreatology and immunology have allowed many of the apparently divergent concepts to be uniﬁed. In 1999, Whitcomb [61] introduced the Sentinel Acute Pancreatitis Event hypothesis based on observations in hereditary pancreatitis compared to alcoholic chronic pancreatitis [35]. It has been recognized that the normal pancreas exposed to alcohol does not develop gross pathologic changes, but that chronic alcohol exposure stresses the acinar cells continuously, resulting in elevation of stress cytokines, oxidative stress and mitochondrial damage [56, 62, 63]. However, at this point, there are few local inﬂammatory effector cells within the pancreatic parenchyma to respond to these signals. According to this concept, an episode of acute pancreatitis may represent the important mechanism leading to the recruitment of immunocytes into the pancreatic tissue and activation of pancreatic stellate cells. This has been named the ‘sentinel’ event because it foresees the beginning of chronic pancreatitis. It was suggested that acute pancreatitis has two phases: an early pro-inﬂammatory phase, and a later anti-inﬂammatory phase. During the ﬁrst phase of acute pancreatitis, pancreatic autodigestion occurs and leads to activation of the inﬂammatory process with release of cytokines, recruitment of neutrophils, monocytes and lymphocytes into the pancreas and activation of pancreatic stellate cells. During this phase, proinﬂammatory cytokines such as tumor necrosis factor- may play a dominant role in mediating tissue destruction. The latter phase might be critical in limiting the inﬂammatory reaction and initiating the healing process. It has been proposed that during this phase the monocytes become tissue macrophages which remain within the pancreas. This phase may be driven by anti-inﬂammatory cytokines such as interleukin-10 or transforming growth factor- and may lead to the deposition of matrix proteins by activated stellate cells as part of the healing process [64–67]. Under normal conditions, acute pancreatitis resolves, and the pancreas returns to normal with the tissue macrophages and activated stellate cells slowly diminishing. In contrast, with recurrent injury to the pancreas, for example by repeated episodes of acute pancreatitis in hereditary pancreatitis or with ongoing consumption of alcohol, the pancreas may react differently compared to the

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pancreas prior to the sentinel event. Now, the continued release of cytokines from stressed acinar cells appears to be followed with an anti-inﬂammatory response from tissue macrophages and pancreatic stellate cells [68]. Thus, the ﬁbrosis in chronic pancreatitis might be driven by transforming growth factor- and other anti-inﬂammatory cytokines. In summary, the Sentinel Acute Pancreatitis Event hypothesis encompasses elements of the necrosis-ﬁbrosis sequence hypothesis, the toxic-metabolic hypothesis, the oxidative stress hypothesis, the duct obstruction hypothesis, and similar approaches.

Future Perspectives

Recent genetic studies of the cationic trypsinogen (PRSS1) gene, the cystic ﬁbrosis transmembrane conductance regulator (CFTR) gene, and the serine protease inhibitor Kazal type 1 (SPINK1) gene revealed major insights into the development of hereditary, idiopathic and tropical pancreatitis [34, 69–74]. However, genetic predispositions in the PRSS1 and SPINK1 genes do not appear to play a dominant role in alcoholic pancreatitis [75– 77], and the role of CFTR mutations in alcoholic pancre-

atitis has not yet been clariﬁed since most of the studies did not investigate the entire gene [78]. Thus, future genetic studies remain important. Future research projects may also aim at studying the role of the brain-gut axis in the development of alcoholic chronic pancreatitis [79]. Since pancreatic exocrine secretion is controlled both by the nervous system and hormones, investigations of the effects of alcohol on the neural mechanisms in mediating pancreatic function might be important for the understanding of alcoholic pancreatitis [79–82]. In conclusion, the exact mechanisms underlying alcoholic chronic pancreatitis are not yet clariﬁed, but it is likely that several mechanisms, for example genetic predispositions or environmental factors such as smoking, act together with alcohol exposure and increase the risk to develop chronic pancreatitis. Finally, future research efforts must aim at the development of more effective means of early detection, early diagnosis and early treatment of the disease.

Acknowledgment This work was supported by the Dietmar-Hopp-Foundation, Walldorf, Germany.

References 1 Friedreich N: Disease of the pancreas; in Ziemssen H (ed): Cyclopoedia of the Practice of Medicine. New York, Wood, 1878, pp 549– 630. 2 Worning H: Alcoholic chronic pancreatitis; in Beger HG, Warshaw AL, Buchler MW (eds): The Pancreas. Malden, Blackwell Science, 1998, pp 672–682. 3 Gastard J, Joubaud F, Farbos T, Loussouarn J, Marion J, Pannier M, Renaudet F, Valdazo R, Gosselin M: Etiology and course of primary chronic pancreatitis in western France. Digestion 1973;9:416–428. 4 Durbec J, Sarles H: Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein, and lipid consumption. Digestion 1978;18:337–350. 5 Copenhagen Pancreatitis Study: An interim report from a prospective multicentre study. Scand J Gastroenterol 1981;16:305. 6 Dani R, Penna FJ, Nogueira CE: Etiology of chronic calcifying pancreatitis in Brazil: a report of 329 consecutive cases. Int J Pancreatol 1986;1:399–406.

Alcoholic Pancreatitis

7 Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP: The different courses of early and late onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994;107:1481–1487. 8 Singer MV, Müller MK: Epidemiologie, Ätiologie und Pathogenese der chronischen Pankreatitis; in Mössner J, Adler G, Fölsch UR, Singer MV (eds): Erkrankungen des exkretorischen Pankreas. Jena, Fischer, 1995, pp 313– 324. 9 Pitchumoni CS, Glasser M, Saran RM, et al: Pancreatic ﬁbrosis in chronic alcoholics and nonalcoholics without clinical pancreatitis. Am J Gastroenterol 1984;79:382–388. 10 Suda K, Shiotsu H, Nakamura T, Akai J, Nakamura T: Pancreatic ﬁbrosis in patients with chronic alcohol abuse: Correlation with alcoholic pancreatitis. Am J Gastroenterol 1994; 89:2060–2062. 11 Gumaste VV: Alcoholic pancreatitis: unraveling the mystery. Gastroenterology 1995; 108: 297–299. 12 Caradonna P, Costamagna G, Benedetti G, Gentiloni N, Gasbarrini GB: Chronic pancreatitis prevalence in liver cirrhosis. Morphological and functional study. Ital J Gastroenterol 1996;28:91–94.

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13 Corrao G, Bagnardi V, Zambon A, Arico S: Exploring the dose-response relationship between alcohol consumption and the risk of several alcohol-related conditions: a meta-analysis. Addiction 1999;94:1551–1573. 14 Ammann RW, Muellhaupt B: The natural history of pain in alcoholic chronic pancreatitis. Gastroenterology 1999;116:1132–1140. 15 Ammann RW, Heitz PU, Klöppel G: Course of alcoholic chronic pancreatitis: a prospective clinicomorphological long-term study. Gastroenterology 1996;111:224–231. 16 Lowenfels AB, Maisonneuve P, Grover H, Gerber E, Korsten MA, Antunes MT, Marques A, Pitchumoni CS: Racial factors and the risk of chronic pancreatitis. Am J Gastroenterol 1999;94:790–794. 17 Marks IN, Bank S: The etiology, clinical features and diagnosis of pancreatitis in the South Western Cape: a review of 243 cases. S Afr Med J 1963;37:1039–1053. 18 Ammann RW: A clinically based classiﬁcation system for alcoholic chronic pancreatitis: Summary of an international workshop on chronic pancreatitis. Pancreas 1997;14:215–221.

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19 Wilson JS, Bernstein L, McDonald C, Tait A, McNeil D, Pirola RC: Diet and drinking habits in relation to the development of alcoholic pancreatitis. Gut 1985;26:882–887. 20 Haber P, Wilson J, Apte M, Korsten M, Pirola R: Individual susceptibility to alcoholic pancreatitis: still an enigma. J Lab Clin Med 1995; 125:305–312. 21 Schneider A, Haas SL, Pfützer RH, Narcovics H, Mann K, Singer MV: Characterization of drinking patterns in patients with alcoholic chronic pancreatitis. Pancreas 2003;27:408. 22 Ammann RW, Muellhaupt B, Meyenberger C, Heitz PU: Alcoholic nonprogressive chronic pancreatitis: prospective long-term study of a large cohort with alcoholic acute pancreatitis (1976–1992). Pancreas 1994;9:365–373. 23 Ammann RW, Muellhaupt B: Progression of alcoholic acute to chronic pancreatitis. Gut 1994;35:552–556. 24 Girdwood AH, Marks IN, Bornman PC, Kottler RE, Cohen M: Does progressive pancreatic insufﬁciency limit pain in calciﬁc pancreatitis with duct stricture or continued alcohol insult? J Clin Gastroenterol 1981;3:241–245. 25 Lankisch PG, Seidensticker F, Lohr-Happe A, Otto J, Creutzfeldt W: The course of pain is the same in alcohol- and nonalcohol-induced chronic pancreatitis. Pancreas 1995; 10: 338– 341. 26 Ammann RW, Akovbiantz A, Largiader F, Schueler G: Course and outcome of chronic pancreatitis. Longitudinal study of a mixed medical-surgical series of 245 patients. Gastroenterology 1984;86:820–828. 27 DiMagno EP, Go VL, Summerskill WH: Relations between pancreatic secretory enzyme outputs and malabsorption in severe pancreatic insufﬁciency. N Engl J Med 1973; 288: 813–815. 28 Levitt NS, Adams G, Salmon J, et al: The prevalence and severity of microvascular complications in pancreatic diabetes and IDDM. Diabetes Care 1995;18:971. 29 Gullo L, Barbara L, Labo G: Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology 1988;95:1063–1068. 30 Strum WB: Abstinence in alcoholic chronic pancreatitis. Effect on pain and outcome. J Clin Gastroenterol 1995;20:37–41. 31 Hanck C, Singer MV: Does acute alcoholic pancreatitis exist without preexisting chronic pancreatitis? Scand J Gastroenterol 1997; 32: 625–626. 32 Klöppel G, Maillet B: Chronic pancreatitis: evolution of the disease. Hepatogastroenterology 1991;38:408–412. 33 Klöppel G, Maillet B: Pseudocysts in chronic pancreatitis: a morphological analysis of 57 resection specimens and 9 autopsy pancreata. Pancreas 1991;6:266–274.

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34 Whitcomb DC, Gorry MC, Preston RA, Furey W, Sossenheimer MJ, Ulrich CD, Martin SP, Gates LK, Amann ST, Toskes PP, Liddle R, McGrath K, Uomo G, Post JC, Ehrlich GD: Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 1996;14:141–145. 35 Schneider A, Whitcomb DC: Hereditary pancreatitis: a model for inﬂammatory diseases of the pancreas. Best Pract Res Clin Gastroenterol 2002;16:347–363. 36 Deng X, Wang L, Elm MS, Gabazadeh D, Diorio GJ, Eagon PK, Whitcomb DC: Chronic alcohol consumption accelerates ﬁbrosis in response to cerulein-induced pancreatitis in rats. Am J Pathol 2005;166:93–106. 37 Renner IG, Savage WT, Pantoja JL, Renner VJ: Death due to acute pancreatitis: a retrospective analysis of 405 autopsy cases. Dig Dis Sci 1985;30:1005–1018. 38 Apte MV, Wilson JS: Alcohol-induced pancreatic injury. Best Pract Res Clin Gastroenterol 2003;17:593–612. 39 Klöppel G, Maillet B: Pathology of chronic pancreatitis; in Beger HG, Warshaw AL, Buchler MW (eds): The Pancreas. Malden, Blackwell Science, 1998, p 720. 40 Klöppel G, Bommer G, Commandeur G, Heitz P: The endocrine pancreas in chronic pancreatitis. Immunocytochemical and ultrastructural studies. Virchows Arch 1978; 377: 157–174. 41 Stolte M: Chronische Pankreatitis. Verh Dtsch Ges Pathol 1987;71:175–186. 42 Bockman DE, Buchler M, Malfertheiner P, Beger HG: Analysis of nerves in chronic pancreatitis. Gastroenterology 1988;94:1459–1469. 43 Noronha M, Dreiling DA, Bordalo OR: Sequential changes from minimal pancreatic inﬂammation to advanced alcoholic pancreatitis. Z Gastroenterol 1983;21:666–673. 44 Singer MV, Gyr K, Sarles H: Revised classiﬁcation of pancreatitis. Gastroenterology 1985;89: 683–690. 45 Schneider A, Whitcomb DC, Singer MV: Animal models in alcoholic pancreatitis – what can we learn? Pancreatology 2002;2:189–203. 46 Perides G, Tao X, West N, Sharma A, Steer ML: A mouse model of ethanol dependent pancreatic ﬁbrosis. Gut 2005;54:1461–1467. 47 Niebergall-Roth E, Harder H, Singer MV: A review: acute and chronic effects of ethanol and alcoholic beverages on the pancreatic exocrine secretion in vivo and in vitro. Alcohol Clin Exp Res 1998;22:1570–1583. 48 Chiari H: Über Selbstverdauung des menschlichen Pancreas. Z Heilkunde 1896;17:69–95. 49 Comfort MW, Gambill EE, Baggenstoss AH: Chronic relapsing pancreatitis: a study of 29 cases without associated disease of the biliary or gastro-intestinal tract. Gastroenterology 1946;6:239–285, 376–408. 50 Sarles H: Deﬁnitions and classiﬁcations of pancreatitis. Pancreas 1991;6:470–474. 51 Sarles H, Bernard JP, Johnson C: Pathogenesis and epidemiology of chronic pancreatitis. Annu Rev Med 1989;40:453–468.

52 De Caro A, Multigner L, Dagorn JC, et al: The human pancreatic stone protein. Biochimie 1988;70:1209–1214. 53 Bimmler D, Graf R, Scheele GA, Frick TW: Pancreatic stone protein (lithostatine), a physiologically relevant pancreatic calcium carbonate crystal inhibitor? J Biol Chem 1997; 272: 3073–3082. 54 Bordalo O, Goncalves D, Noronha M, Cristina ML, Salgadinho A, Dreiling DA: Newer concept for the pathogenesis of chronic alcoholic pancreatitis. Am J Gastroenterol 1977; 68: 278–285. 55 Pfützer RH, Tadic SD, Li HS, Thompson BS, Zhang JY, Ford ME, Eagon PK, Whitcomb DC: Pancreatic cholesterol esterase, ES-10, and fatty acid ethyl ester synthase III gene expression are increased in the pancreas and liver but not in the brain or heart with long-term ethanol feeding in rats. Pancreas 2002;25:101– 106. 56 Gukovskaya AS, Mouria M, Gukovsky I, Reyes CN, Kasho VN, Faller LD, Pandol SJ: Ethanol metabolism and transcription factor activation in pancreatic acinar cells in rats. Gastroenterology 2002;122:106–118. 57 Braganza JM: Pancreatic disease: a casualty of hepatic ‘detoxiﬁcation’? Lancet 1983;ii:1000– 1003. 58 Van Gossum A, Closset P, Noel E, Cremer M, Neve J: Deﬁciency in antioxidant factors in patients with alcohol-related chronic pancreatitis. Dig Dis Sci 1996;41:1225–1231. 59 Norton ID, Apte MV, Lux O, Haber PS, Pirola RC, Wilson JS: Chronic ethanol administration causes oxidative stress in the rat pancreas. J Lab Clin Med 1998;131:442–446. 60 Ammann RW, Buehler H, Bruehlmann W, Kehl O, Muench R, Stamm B: Acute (nonprogressive) alcoholic pancreatitis: prospective longitudinal study of 144 patients with recurrent alcoholic pancreatitis. Pancreas 1986; 1: 195–203. 61 Whitcomb DC: Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 1999;45:317–322. 62 Li HS, Deng XY, Thompson BS, Zhang JY, Wood PG, Eagon PK, Whitcomb DC: Chronic ethanol consumption induces gene expression of pancreatic monitor peptide, but not SPINK1/PSTI-56, in rats. Pancreas 2001; 23: 117–124. 63 Grattagliano I, Palmieri V, Vendemiale G, Portincasa P, Altomare E, Palasciano G: Chronic ethanol administration induces oxidative alterations and functional impairment of pancreatic mitochondria in the rat. Digestion 1999;60:549–553. 64 Van Laethem J, Deviere J, Resibois A, et al: Localization of transforming growth factor beta 1 and its latent binding protein in human chronic pancreatitis. Gastroenterology 1995; 108:1873–1881.

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65 Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, Siech M, Beger H, Grunert A, Adler G: Identiﬁcation, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology 1998; 115:421–432. 66 Apte MV, Haber PS, Applegate TL, Norton ID, McCaughan GW, Korsten MA, Pirola RC, Wilson JS: Periacinar stellate shaped cells in rat pancreas: identiﬁcation, isolation, and culture. Gut 1998;43:128–133. 67 Schmid-Kotsas A, Gross HJ, Menke A, et al: Lipopolysaccharide-activated macrophages stimulate the synthesis of collagen type I and C-ﬁbronectin in cultured pancreatic stellate cells. Am J Pathol 1999;155:1749–1758. 68 Apte M, Phillips P, Fahmy R, Darby SJ, Rodgers SC, McCaughan GW, Korsten MA, Pirola RC, Naidoo D, Wilson JS: Does alcohol directly stimulate pancreatic ﬁbrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology 2000;118:780–794. 69 Cohn JA, Friedmann KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS: Relation between mutations of the cystic ﬁbrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339:653–658. 70 Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, Braganza J: Mutations of the cystic ﬁbrosis gene in patients with chronic pancreatitis. N Engl J Med 1998; 339: 645– 652.

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71 Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, Landt O, Becker M: Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25:213–216. 72 Pfützer RH, Barmada MM, Brunskill AP, Finch R, Hart PS, Neoptolemos J, Furey WF, Whitcomb DC: SPINK1/PSTI polymorphisms act as disease modiﬁers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000;119:615–623. 73 Chandak GR, Idris MM, Reddy DN, Bhaskar S, Sriram PV, Singh L: Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/ SPINK1) rather than the cationic trypsinogen gene (PRSS1) are signiﬁcantly associated with tropical calciﬁc pancreatitis. J Med Genet 2002;39:347–351. 74 Schneider A, Suman A, Rossi L, Barmada MM, Beglinger C, Parvin S, Sattar S, Ali L, Azad Kahn A, Gyr N, Whitcomb DC: SPINK1/ PSTI mutations are associated with tropical pancreatitis and type II diabetes mellitus in Bangladesh. Gastroenterology 2002; 123: 1026–1030. 75 Teich N, Mössner J, Keim V: Screening for mutations of the cationic trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut 1999;44:413–416.

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76 Schneider A, Pfutzer RH, Barmada MM, Slivka A, Martin J, Whitcomb DC: Limited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis: a report from the United States. Dig Dis Sci 2003;48:1110–1115. 77 Schneider A: Serine protease inhibitor Kazal type 1 mutations and pancreatitis. Gastroenterol Clin North Am 2004;33:789–806. 78 Hanck C, Schneider A, Whitcomb DC: Genetic polymorphisms in alcoholic pancreatitis. Best Pract Res Clin Gastroenterol 2003; 17: 613–623. 79 Siegmund S, Spanagel R, Singer MV: Role of the brain-gut axis in alcohol related gastrointestinal diseases – what can we learn from new animal models? J Physiol Pharmacol 2003; 54(suppl 4):191–207. 80 Banuelos-Pineda J, Carmona-Calero E, PerisSanchis R, Perez-Gonzales H, Marrero-Gordillo N, Perez-Delgado MM, Castancyra-Perdomo A: Alcohol intake effects on the dorsal vagal complex of the rat: A cellular morphometric study. Acta Anat 1995;153:145–150. 81 Deng X, Guarita DR, Pedroso MR, Kreiss C, Wood PG, Sved AF, Whitcomb DC: PYY inhibits CCK-stimulated pancreatic secretion through the area postrema in unanesthetized rats. Am J Physiol 2001;281:R645–R653. 82 Deng X, Wood PG, Eagon PK, Whitcomb DC: Rapid adaptation of pancreatic exocrine secretion to short-term alcohol feeding in rats. Pancreatology 2005;5:183–195.

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and type of alcohol consumed [6, 7], the pattern of alcohol consumption [6], lipid intolerance [8] and smoking [9, 10]. Inherited factors have also been studied. These are detailed elsewhere in this book and therefore not individually referenced here. They include blood group antigens, HLA serotypes, 1-antitrypsin phenotypes, cystic ﬁbrosis genotype, genotypes of cytokines (tumor necrosis factor- (TNF-), transforming growth factor- (TGF), interleukin-10), genotypes of alcohol-metabolizing enzymes (alcohol dehydrogenase (ADH), cytochrome P4502E1 (CYP2E1)), genotypes of enzymes that detoxify metabolites of alcohol (such as glutathione S transferases), and mutations of genes related to pancreatic proteins that may play an important role in autodigestive injury to the gland (these include digestive enzymes and proteins that can inactivate digestive enzymes such as pancreatic secretory trypsin inhibitor, mesotrypsin and enzyme Y). Generally speaking, these studies into individual susceptibility have failed to provide a uniform explanation for the majority of cases of alcoholic pancreatitis. Most recently, a positive association has been reported between the risk of developing alcoholic pancreatitis and a polymorphism of the carboxyl ester lipase (CEL) gene [11]. CEL, a digestive enzyme secreted by the exocrine pancreas, catalyses the synthesis of fatty acid ethyl esters (FAEEs) from fatty acids and ethanol. As discussed in detail below, FAEEs are non-oxidative metabolites of ethanol that are thought to play a signiﬁcant role in pancreatic acinar cell injury. While the reported association of a CEL gene polymorphism and alcoholic pancreatitis is of considerable interest, it must be noted that the functional signiﬁcance of the polymorphism is yet to be elucidated. Thus, the search for individual susceptibility factors continues.

Constant Effects of Alcohol on the Pancreas

The remainder of this article will be conﬁned to the constant effects of alcohol on the pancreas. Over the past 30 years, the focus of research in this area has shifted from the sphincter of Oddi to small pancreatic ducts and subsequently to the pancreatic acinar cell itself. The role of the sphincter of Oddi in alcoholic pancreatitis remains unclear principally due to a lack of consensus about the effects of alcohol on sphincter activity. In humans, both decreased [12, 13] and increased [14] sphincter of Oddi activity in response to alcohol have been reported. Studies with experimental animals support the latter ﬁnding, i.e. a ‘spasmogenic’ effect of alcohol on the sphincter [15].

Molecular Mechanisms of Alcoholic Pancreatitis

In this regard, a recent study has reported a signiﬁcant reduction in transsphincteric ﬂow in possums treated with intravenous ethanol [16]. Thus, alcohol-induced sphincter of Oddi spasm may be one of the mechanisms responsible for the decrease in pancreatic secretion observed after acute alcohol administration in humans [17]. In the early 1970s, the focus of attention moved to small pancreatic ducts. Sarles [18, 19] proposed that alcoholic pancreatitis is caused by the blockage of small ducts by protein plugs (formed by the precipitation of secreted pancreatic proteins) leading to acinar atrophy and ﬁbrosis. The main reservation regarding the protein plug theory is the lack of clear evidence that protein precipitation within pancreatic ducts precedes acinar damage. This has made it difﬁcult to determine whether protein plugs are a cause or an effect of pancreatic injury. However, the possibility that acinar and ductal changes occur simultaneously in alcoholic pancreatitis and play a synergistic role in the development and progression of the disease cannot be ruled out. As early as in 1965, Sarles et al. [20] reported that patients with alcoholic pancreatitis manifest increased levels of sweat electrolytes (chloride and sodium), suggesting cystic ﬁbrosis transmembrane regulator dysfunction in this disease. On the other hand, alcohol has been shown to induce changes in acinar cell function that may potentiate the formation of protein plugs via increased synthesis of proteins known to have a tendency to precipitate in pancreatic juice, such as lithostathine and glycoprotein 2 (GP2). Over the past few years, researchers have turned their attention to the pancreatic acinar cell itself as a possible initial site of injury in alcoholic pancreatitis. This focus is understandable given that the cell produces large amounts of digestive enzymes with the potential to cause considerable tissue damage. Taking their cues from studies of ethanol toxicity in the liver [21], investigators have postulated that ethanol metabolism by the pancreatic acinar cell and the resulting molecular alterations in the cell predispose the cell to signiﬁcant injury. The ﬁndings that support this concept are detailed below.

Ethanol Metabolism by Pancreatic Acinar Cells

It is now established that the pancreas has the capacity to metabolize ethanol. Previous studies in the liver have shown that there are two major pathways of ethanol metabolism, oxidative and non-oxidative. These generate

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the metabolites acetaldehyde and FAEEs, respectively [22–24]. Oxidative ethanol metabolism involves the conversion of ethanol to acetaldehyde, a reaction that is catalyzed by ADH with contributions from CYP2E1 and possibly also catalase. Non-oxidative metabolism of ethanol involves its conversion to FAEEs via FAEE synthases. Oxidative Pathway ADH In cultured pancreatic acinar cells, Haber et al. [22] used ion exchange chromatography to demonstrate oxidation of 14C-ethanol to its oxidative product 14C-acetate. The rate of ethanol oxidation (particularly at high concentrations of 50 mM) was comparable to that observed in hepatocytes cultured under the same conditions. These investigators also provided evidence (via studies on the kinetics of ethanol oxidation and the use of speciﬁc ADH inhibitors) that the observed ethanol oxidation is mediated by the class III isotype of ADH. A subsequent study by Gukovskaya et al. [23] using isolated pancreatic acini has corroborated the above ﬁndings. Gukovskaya et al. have demonstrated that pancreatic ADH has a high Km for ethanol and is not inhibited by 4-methylpyrazole (an ADH class I and II inhibitor), supporting the conclusion that the ADH isoform in pancreatic acinar cells is most likely ADH III. CYP2E1 As noted earlier, another enzyme that plays a role in ethanol oxidation, particularly at high ethanol concentrations and after chronic ethanol consumption, is CYP2E1. The presence of CYP2E1 has been demonstrated in rat pancreas [25] as well as in human pancreas [26] by immunoblotting and immunohistochemical techniques, respectively. Moreover, chronic ethanol administration has been shown to induce the expression of CYP2E1 in the rat pancreas [25], an effect similar to that described in the liver [27]. Despite this, CYP2E1 has not been found to contribute appreciably to pancreatic ethanol oxidation (based on enzyme inhibitor studies) in cultured pancreatic acinar cells [22]; however, it must be noted that this was an acute study examining the effect of ethanol on acinar cells isolated from chow-fed animals. In order to fully delineate the role of CYP2E1 in the pancreas, it would be necessary to examine ethanol oxidation in acinar cells isolated from rat pancreas where CYP2E1 has been induced by chronic ethanol administration.

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Non-Oxidative Pathway FAEEs With regard to the non-oxidative pathway of ethanol metabolism, there is evidence that FAEEs accumulate in both the human [28] and rat pancreas [29] after ethanol consumption. It is likely that this accumulation is due to the generation of the compounds within the pancreas itself. This notion is supported by studies showing the formation of FAEEs in isolated pancreatic acini incubated with ethanol [23, 24] and the demonstrated presence of FAEE synthase activity in the pancreas [23, 30]. Candidate FAEE synthase enzymes in the pancreas are CEL and triglyceride lipase. Pancreatic CEL has been shown to exhibit FAEE synthetic activity and can therefore be conﬁrmed as a FAEE synthase [31]. However, the FAEE synthetic activity of triglyceride lipase has not yet been fully characterized. Relative Contributions of Pathways of Pancreatic Ethanol Metabolism The established ability of the pancreas to metabolize ethanol via both oxidative and non-oxidative pathways, has prompted investigators to examine (i) the relative contribution of the two pathways to pancreatic ethanol metabolism, and (ii) the possible metabolic link between the pathways (i.e. whether inhibition of one of the pathways causes an increase in the ﬂux of ethanol metabolism through the other). The rate of oxidative metabolism of ethanol in the pancreas has been found to be consistently higher than that of non-oxidative metabolism of ethanol [23, 24]. However, this ﬁnding does not necessarily diminish the signiﬁcance of non-oxidative metabolism of ethanol within the pancreas, because tissue levels of the products (FAEEs) generated by this pathway have been shown to be sufﬁcient to cause injury to subcellular organelles within the gland (vide infra) [32]. The possibility of a metabolic link between the two pathways of ethanol metabolism has been examined by Werner et al. by both in vitro [30] and in vivo [33] studies. The authors report that, in rat pancreatic homogenates incubated with ethanol in the presence of inhibitors of oxidative metabolism, the formation of FAEEs was increased compared to that in the absence of the inhibitors. However, inhibition of oxidative metabolism per se and/or inhibition of relevant enzymes (particularly ADH) was not measured in this experimental setting, preventing a ﬁrm conclusion as to the existence of a metabolic link between the two pathways. More recently, Werner et al. [33] have reported an in vivo study where acute infusion of ethanol and inhibitors of oxidative metabolism led to

Apte/Pirola/Wilson

increased FAEE accumulation in rat pancreas. In this study, pancreatic ADH activity was shown to be inhibited by 4-methylpyrazole suggesting the presence ADH I (a saturable isoform of ADH with low Km for ethanol) in the pancreas. This ﬁnding contrasts with previous inhibitor studies demonstrating that the isoform of ADH in pancreatic acini is ADH III. Thus, the contention that the two pathways are metabolically linked needs further clariﬁcation. However, regardless of the presence or absence of a metabolic link between the two pathways, it is highly likely (as discussed below) that pancreatic ethanol metabolism and the consequent generation of toxic metabolites play a role in ethanol-induced pancreatic injury.

Evidence that Ethanol Administration Induces Pancreatic Injury

Animal models of both acute and chronic ethanol administration have been employed to study alcohol-related morphological and metabolic changes in the pancreas. These are discussed in detail elsewhere and therefore only a summary of the salient ﬁndings is provided here. Acute in vivo infusion of ethanol to rats has been reported to cause dose-dependent injury to the pancreas characterized by pancreatic edema, acinar vacuolization and activation of trypsinogen [33]. Chronic (continuous) intragastric infusion of ethanol with high dietary fat for 4 weeks has also been reported to cause pancreatic edema and focal changes including inﬂammatory cell inﬁltration and acinar necrosis [34]. However, the ‘unphysiological’ nature of ethanol administration in this model is a drawback. The Lieber-DeCarli pair-feeding model represents a more physiological method of chronic ethanol feeding than the intragastric model, since it allows ad libitum intake of an ethanol-containing liquid diet [35]. This method of ethanol administration does not produce overt pancreatic injury, but has been shown to induce a number of metabolic changes within the cell [36]. These include a signiﬁcant increase in the content of digestive enzymes and lysosomal enzymes within the acinar cell, accompanied by a signiﬁcant decrease in the stability of the organelles that contain these enzymes (zymogen granules and lysosomes, respectively). Basal pancreatic (acinar cell) secretion has recently been reported to be inhibited in ethanol-fed rats [37]. Inhibition of pancreatic secretion due to ethanol may occur at several levels including the sphincter of Oddi (spasm) [14, 15], pancreatic ducts (protein plug formation) [5] and acinar cells (disturbances in exocytosis possibly due to acetaldehyde-induced micro-

Molecular Mechanisms of Alcoholic Pancreatitis

tubular dysfunction [38] or to ethanol-induced reorganization of F-actin in the apical cytoskeleton of acinar cells as has been described in a recent in vitro study using isolated acini [39]). A decrease in acinar secretion may further increase the content of digestive enzymes in the cells. This increase in enzyme content together with the increased potential for contact between lysosomal enzymes (particularly cathepsin B, known to be capable of activating trypsinogen [40, 41]) and digestive enzymes could result in premature intracellular activation of digestive enzymes and, in the presence of an (as yet unknown) triggering agent, an overt attack of pancreatitis. One of the candidate trigger factors that has been investigated is cholecystokinin (CCK). Early studies with CCK have provided conﬂicting results with chronic ethanol administration reported to either intensify [42] or have no effect [43] on the severity of CCK-induced pancreatitis in rats. A later report indicates that chronic ethanol administration via gastrostomy catheters sensitizes the rat pancreas to the development of CCK-induced pancreatitis [44]. This effect has been recently conﬁrmed by Perides et al. [45] in mice using the more physiological Lieber-DeCarli model of chronic ethanol administration. Viral infection has recently been postulated as another triggering factor for alcoholic pancreatitis. In this regard, Clemens and Jerrells [46] have reported that mice receiving the Lieber-DeCarli ethanol diet demonstrated increased pancreatic injury upon infection with Coxsackie B virus compared to pair-fed controls. In addition to the alterations in pancreatic digestive enzymes, chronic ethanol feeding has also been reported to induce changes in two ‘non-digestive’ pancreatic proteins (lithostathine and GP2) that may be relevant to protein plug formation within pancreatic ductules. Chronic ethanol administration increases the capacity of the pancreas to synthesize lithostathine [47]. As noted earlier, lithostathine is a major component of protein plugs. It is postulated that the increased synthesis of lithostathine may lead to increased concentrations of the protein in pancreatic juice. Hydrolysis of native lithostathine in pancreatic juice by proteases such as trypsin is known to generate lithostathine S1 – a form of lithostathine that polymerizes at neutral pH forming a nucleation site/nidus for further protein deposits. Chronic ethanol administration has also been shown to decrease the content of GP2 in pancreatic homogenates [48]. One of the mechanisms responsible for the reduction in pancreatic GP2 content is increased secretion into pancreatic juice. GP2 is known to form ﬁbrillar aggregates within the juice that may form a nidus for protein and calcium precipitation.

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Thus alcohol-induced alterations in acinar cell secretion of lithostathine and GP2 may potentiate protein plug formation within pancreatic ducts.

How Does Ethanol Metabolism Cause Pancreatic Injury by Acinar Cells?

Ethanol metabolism within the pancreas has the potential to contribute signiﬁcantly to the ethanol-related pancreatic damage via direct effects of the metabolites acetaldehyde and FAEEs, and/or via metabolic alterations induced within the cells such as changes in the intracellular redox state and the generation of oxidant stress. Acetaldehyde (albeit at high concentrations) has been shown to cause morphological damage to both the rat and dog pancreas [49, 50]. It has also been reported to inhibit stimulated secretion from isolated pancreatic acini [38, 51]. This inhibition is thought to be secondary to interference with the binding of secretagogues to their receptors [51] and possibly, microtubular dysfunction affecting exocytosis from the acinar cell [38]. During the oxidation of ethanol to acetaldehyde, and subsequently acetate, hydrogen ions (reducing equivalents) are released [21, 52]. This alters the intracellular redox state of the cell (as indicated by a reduced [NAD]/[NADH] ratio and increased [lactate]/ [pyruvate] ratio) leading to a number of metabolic alterations that could contribute to acinar injury [21]. Oxidant stress is another important consequence of ethanol oxidation that may play a role in pancreatic injury. Both acute and chronic ethanol exposures are known to cause oxidant stress in the rat pancreas [53, 54]. Evidence of oxidant stress has also been reported in the pancreas of patients with alcoholic chronic pancreatitis [55, 56]. In general, oxidant stress results from an imbalance between the production of free radicals or reactive oxygen species (highly reactive molecules with the potential to damage lipid membranes, intracellular proteins and DNA) and the antioxidant defense mechanisms within the cell (including glutathione, the enzymes glutathione peroxidase, superoxide dismutase and catalase and their co-factors such as vitamin C, vitamin E, zinc and selenium). The mechanisms responsible for oxidant stress secondary to ethanol exposure include acetaldehyde-induced depletion of reduced glutathione [57, 58] and the increased generation of free radicals during the metabolism of ethanol via CYP2E1 [59]. FAEEs, products of non-oxidative ethanol metabolism, have been shown to induce pancreatic injury in vivo

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[60] as well as in vitro [32]. Werner et al. [60] have reported that infusion of FAEEs into rats leads to pancreatic edema, acinar vacuolization and activation of trypsinogen, while Haber et al. [32] have shown that FAEEs destabilize lysosomes within pancreatic acinar cells. FAEE toxicity may be mediated by (i) direct interaction of the compounds with cellular membranes [61], (ii) release of free fatty acids by hydrolysis of FAEEs (a process thought to contribute to FAEE-induced mitochondrial damage) [62], and (iii) promotion of the synthesis of cholesteryl esters (compounds that are known to accumulate in the rat pancreas after chronic ethanol administration [63] and to destabilize lysosomal membranes in vitro [32]). In summary, evidence from in vivo and in vitro studies indicates that ethanol inﬂuences acinar cell function in a way that predisposes the cell to autodigestive injury. Chronic ethanol exposure (i) increases the content of digestive and lysosomal enzymes within the acinar cell via an increase in synthesis and a decrease in secretion (secondary to inhibition of exocytosis due to microtubular dysfunction and/or F-actin reorganization within the cell); (ii) decreases the stability of the organelles that contain digestive enzymes and lysosomes (possibly mediated via FAEE, cholesteryl esters and/or oxidant stress), and (iii) potentiates protein plug formation within ductules (which could further block acinar secretion and cause local and upstream effects). Taken together, these effects may facilitate the activation of digestive enzymes by lysosomal enzymes within the acinar cell and, in the presence of an appropriate trigger factor, initiate autodigestion.

Progression of Alcoholic Acute Pancreatitis to Chronic Pancreatitis

The histopathological spectrum of alcoholic pancreatitis ranges from acute pancreatitis (acinar necrosis and inﬂammation) to chronic changes involving the loss of acinar cells and ﬁbrosis [64]. Alcoholic pancreatitis has been traditionally thought of as a form of chronic pancreatitis from the start, punctuated during its course by acute exacerbations. This notion was based on studies showing that histological and radiological evidence of chronic pancreatitis was apparent in the pancreas of many patients at the time of their ﬁrst attack of pancreatitis [65, 66]. Furthermore, autopsy studies had reported evidence of pancreatic ﬁbrosis in alcoholics with no clinical history of pancreatitis [67].

Apte/Pirola/Wilson

The above concept has been challenged in recent years, with current opinion favoring the ‘necrosis-ﬁbrosis’ hypothesis that alcoholic pancreatitis begins as an acute process which progresses to chronic irreversible damage as a result of repeated acute attacks. This hypothesis is supported by both clinical and experimental data. A large prospective study has reported that clinical manifestations of chronic pancreatitis (exocrine and endocrine dysfunction) were more likely to occur in alcoholics with clinical recurrent acute inﬂammations [68]. In addition, a postmortem study of patients with fatal alcoholic pancreatitis has demonstrated that in 53% of the patients there was no evidence of chronic changes in the pancreas [69]. Experimental evidence in support of the necrosisﬁbrosis hypothesis has accumulated rapidly in recent years – animal models of pancreatic ﬁbrosis have now been developed by inducing repeated episodes of acute necro-inﬂammation in the pancreas using an inhibitor of superoxide dismutase inhibitor [70] or administration of supraphysiological doses of cerulein with or without other measures such as ethanol administration or pancreatic duct obstruction [44, 45, 71, 72].

Pathogenesis of Alcoholic Pancreatic Fibrosis

Research efforts in elucidating the mechanisms of alcoholic pancreatic ﬁbrosis were given signiﬁcant impetus with the identiﬁcation, isolation and characterization of stellate cells in the pancreas [73–75]. PSCs are morphologically similar to hepatic stellate cells, the principal effector cells in liver ﬁbrosis [76]. It is now established that activated PSCs play a key role in the ﬁbrogenic process via their ability to regulate both the synthesis and degradation of extracellular matrix proteins that comprise ﬁbrous tissue [77]. There is evidence from both clinical and experimental studies indicating a role for PSCs in ethanol-induced pancreatic ﬁbrosis. In vivo studies of tissue from humans with alcoholic pancreatitis and from animals with experimental pancreatic ﬁbrosis have demonstrated the presence of activated PSCs in areas of ﬁbrosis [56, 78, 79]. In vitro studies have established that PSCs are activated directly by ethanol and acetaldehyde as assessed by increased extracellular matrix protein production by the cells [80]. Of particular interest is the observation that rat PSCs exhibit ADH activity [80], indicating that, apart from parenchymal (acinar) cells, ethanol can also be metabolized by non-parenchymal cells in the pancreas. Initial studies using the ADH inhibitor 4-methylpyrazole

Molecular Mechanisms of Alcoholic Pancreatitis

have indicated that the isotype of ADH in PSCs is ADH I (in contrast to the ADH III isotype reported in acinar cells). Further work to characterize the kinetics of ADH activity in PSCs and to examine the non-oxidative pathway of ethanol metabolism in these cells is needed. Activation of PSCs by ethanol can be completely inhibited by the ADH inhibitor 4-methylpyrazole, indicating that ethanol-induced PSC activation is likely mediated by its oxidative metabolite, acetaldehyde. Both ethanol and acetaldehyde have been shown to cause oxidant stress within cultured PSCs, as indicated by increased formation of the lipid peroxidation product malondialdehyde [80]. Incubation of PSCs with ethanol or acetaldehyde in the presence of the antioxidant vitamin E has been shown to prevent the activation of PSCs by the two compounds [80]. These ﬁndings suggest that ethanol-induced PSC activation is most likely mediated by its metabolism (via ADH) to acetaldehyde, and the subsequent generation of oxidant stress within the cells. During prolonged heavy alcohol intake, PSCs could be exposed not only to ethanol and its metabolites but also to pro-inﬂammatory cytokines released during episodes of ethanol-induced pancreatic necro-inﬂammation. Cytokines such as TGF-, platelet-derived growth factor, TNF-, interleukins 1 and 6 and monocyte chemotactic protein are known to be upregulated during acute pancreatitis and each of these has been reported to activate PSCs in vitro [81, 82]. In view of the above, two ﬁbrogenic pathways (acting in parallel) may be proposed to explain the development of alcohol-related pancreatic ﬁbrosis: the necro-inﬂammatory pathway (activation of PSCs by cytokines released during ethanol-induced acinar cell necrosis), and the nonnecro-inﬂammatory pathway (direct activation of PSCs by ethanol via acetaldehyde and/or oxidant stress). The identiﬁcation of a non-necro-inﬂammatory pathway of stellate cell activation implies that tissue necrosis or inﬂammation may not be an absolute prerequisite for the stimulation of ﬁbrogenesis in the pancreas during alcohol abuse. This concept is supported by a recent study which describes activation of hepatic stellate cells in the absence of hepatitis in liver biopsies from alcoholic patients [83].

Signal Transduction Mechanisms in Alcoholic Pancreatitis

In view of the injurious effects of ethanol and its metabolites on parenchymal and non-parenchymal pancreatic cells, attention has recently focused on the cell signal-

Dig Dis 2005;23:232–240

237

Fig. 1. The Drinker’s Pancreas. Diagrammatic representation of the proposed concept for the pathogenesis of alcoholic pancreatitis. It is postulated that ethanol, its metabolites and oxidant stress exert a number of toxic effects on pancreatic acinar cells including: (i) increased digestive and lysosomal (L) enzyme content (due to increased synthesis and decreased secretion), and (ii) decreased stability of lysosomal and zymogen granule (ZG) membranes (mediated by cholesteryl esters (CE), FAEEs, oxidant stress and decreased GP2). These changes predispose the gland to autodigestive injury and acute necro-inﬂammation (acute pancreatitis). Cytokines released during acute necro-inﬂammatory episodes activate pancreatic stellate cells. These cells may also be activated directly by ethanol (even in the absence of necro-inﬂammation) via its metabolite acetaldehyde and the generation of oxidant stress. Persistent activation of PSCs (due to repeated necro-inﬂammatory episodes and/or continued ethanol exposure) eventually leads to the development of ﬁbrosis in the gland (chronic pancreatitis). mRNA = Messenger RNA; Ac = acetaldehyde.

Cytokines

Enzyme activation Stellate cell activation

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L

ZG ? GP2

Oxidant stress Oxidant stress

ing pathways that may be responsible for mediating the observed changes. In this regard, Gukovskaya et al. [23, 84] have shown that ethanol and its metabolites acetaldehyde and FAEEs regulate the transcription factors NF-B and AP-1 in parenchymal (acinar) cells, which in turn, regulate pancreatic cytokine expression. With respect to non-parenchymal cells (PSCs), two recent studies have described induction of the mitogen-activated protein kinase pathway (a major pathway regulating protein synthesis in mammalian cells), by ethanol and acetaldehyde [85, 86]. Additional signaling molecules that have been recently implicated in ethanol-induced PSC activation include PI3 kinase and protein kinase C [87, 88]. It is envisaged that identiﬁcation of relevant signaling molecules may enable speciﬁc pathways to be therapeutically targeted so as to prevent/reduce the deleterious effects of ethanol on the pancreas.

238

Necrosis

? mRNA

Ac CE&FAEE Ac

ETHANOL

Current Concept of the Molecular Mechanisms of Alcoholic Pancreatitis

The ﬁndings of clinical and experimental studies related to alcohol and the pancreas form the basis of our concept of the drinker’s pancreas (ﬁg. 1). This may be deﬁned as a gland that is predisposed to autodigestive injury due to the effects of ethanol (via its metabolites and its metabolic byproducts) on digestive and lysosomal enzyme content within the acinar cell and on the stability of the organelles that contain these enzymes. In the presence of an appropriate trigger, the above ethanol-induced metabolic changes result in overt pancreatic necrosis. Repeated episodes of acute necro-inﬂammation and the release of pro-inﬂammatory cytokines leads to activation of PSCs. PSCs are also activated directly by ethanol (via its metabolite acetaldehyde and the subsequent generation of oxidant stress). Persistent activation of PSCs leads to an imbalance between extracellular matrix protein synthesis and degradation, eventually resulting in pancreatic ﬁbrosis.

Apte/Pirola/Wilson

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Apte/Pirola/Wilson

Table 1. Treatment of chronic pancreatitis

Basic treatment Cessation of alcohol abuse (psychiatrist, social care worker) Treatment of pain Increasing dosages of analgesic medication step-by-step starting with non-narcotic agents. If this approach is not sufﬁcient, narcotic agents together with adjunctive agents (e.g. antidepressants) are applied Decrease in intrapancreatic pressure by Administration of pancreatic enzymes Therapy of ductal obstruction (endoscopic stent, endoscopic ductal stone removal, surgical duct decompression) Modiﬁcation of neural transmission (celiac plexus block, thoracoscopic splanchnectomy) Surgical intervention if analgesic medication remains insufﬁcient (pancreatic head resection, total or subtotal pancreatectomy Treatment of exocrine insufﬁciency Diet recommendations (intake of 4–5 smaller meals, diet rich in carbohydrates and proteins) Supplementation with pancreatic enzymes Administration of medium-chain triglycerides if enzyme supplementation is not sufﬁcient Supplementation of fat-soluble vitamins and other micronutrients Treatment of endocrine insufﬁciency Diet recommendations (reduction of carbohydrate intake) Administration of insulin (mean blood glucose level between 120 and 150 mg/dl) The management of patients with chronic pancreatitis involves several specialists such as gastroenterologists, surgeons, psychiatrists or social care workers. Patients have to be counseled about the importance of abstinence from alcohol. Abdominal pain is treated with analgesic medication; exocrine insufﬁciency is treated with pancreatic enzyme supplementation, and endocrine insufﬁciency is treated with insulin.

for the development of chronic pancreatitis [1–3]. It has been clearly shown that the rate of progression of the disease is associated with alcohol consumption as well as smoking in patients with alcoholic chronic pancreatitis [4, 5]. Moreover, a reduction in pancreatic pain has been consistently reported [6–8]. One study reported an increase in gastric lipase and thereby a reduction in exocrine insufﬁciency in abstinent patients [9]. Therefore, cessation of alcohol use and smoking are key goals in the treatment of chronic pancreatitis. While total cessation of alcohol is the primary target, at least a reduction in consumption can be achieved in many cases, if the patient is willing to seek professional help. Although equally important, due to the great addictive potential of nicotine, smoking cessation may be much more difﬁcult to achieve, especially in patients with current or past alcohol problems [10, 11].

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Treatment of Pain

In patients with chronic pancreatitis, abdominal pain is the predominant clinical symptom. The causes of abdominal pain can be variable, ranging from conditions such as pseudocysts or duodenal obstruction to concomitant peptic ulceration and may involve mechanisms such as chronic neural inﬂammation [12], ductal hypertension [13] and ischemia [14]. The mechanisms of pain are incompletely understood, and the management often remains frustrating. A central issue is therefore the identiﬁcation of tractable causes of pain such as pseudocysts. As a consequence, the treatment regimens of patients with chronic pancreatitis have to involve several specialists, including physicians, surgeons, psychiatrists or psychologists and social care workers (table 1). The patterns of abdominal pain range from mild abdominal discomfort occurring only once in a while to intractable pain which is continuously present and sig-

Pfützer/Schneider

niﬁcantly reduces the patient’s quality of life. Thus, the treatment of pain has to be managed on an individual basis. Some authors have advised the adaptation of a step-by-step approach in analogy to the WHO threetiered approach for the management of patients with cancer pain [15]. It should be noted that no prospective randomized trial has been carried out to evaluate this approach in patients with chronic pancreatitis. Nevertheless, the WHO ladder has been successfully adapted in many different conditions of chronic pain. In a ﬁrst step, non-steroidal analgesics should be applied, which may be supplemented with adjuvant drugs such as tricyclic antidepressants and serotonin reuptake inhibitors. In the second step, mild opioid analgesics such as codeine or hydrocodone may be added. If pain control is incomplete, opioid dose or potency will have to be increased. Of note, alcohol abstinence reduces the severity of pain attacks and delays deterioration of pancreatic function [16]. Table 2 shows an adaptation of the step-by-step approach as suggested by Mössner et al. [15]. In the past, there have been repeated reports on increased sphincter of Oddi (SOD) pressure following opioid therapy. However, in 2001 a review concluded that virtually all narcotics may increase SOD pressure and that the beneﬁts of morphine treatment may outweigh its risks [17]. A recent study in post-cholecystectomy patients found signiﬁcant differences in SOD pressure and function following analgesic application [18]. Therefore caution may be advised when using potent opioid receptor agonists. The use of partial agonists or agonists/antagonists such as buprenorphin may be beneﬁcial in patients with chronic pancreatitis [19]. The use of pancreatic enzyme supplementation for pain control is based on the hypothesis of negative feedback regulation of pancreatic enzyme secretion [20]. Six randomized controlled trials have been published, one of them in abstract form [20–25]. Four studies have used enteric coated enzyme preparations and yielded negative results. Two studies used non-enteric coated enzymes and proved effective for pain control. However, the studies have been criticized for patient selection or inadequate study size. Nevertheless, the American Gastroenterology Association’s practice guidelines still recommend a trial of enzyme replacement therapy for pain control [26], and this practice has been widely used in the clinical setting. Experimental therapeutic options include for example treatment with antioxidants, based on the observation that oxygen-derived free radicals are increased in in vitro and in vivo models of acute and chronic pancreatitis, and

Treatment of Alcoholic Pancreatitis

Table 2. Step-by-step approach to the treatment of pain in chronic pancreatitis according to Mössner et al. [15]

Step 1 Supportive measures Elimination of alcohol, dietary recommendations Step 2a Peripheral analgesics e.g. Acetaminophen 500 mg q.i.d. Step 2b Peripheral plus opioid analgesics e.g. Step 2a plus Tramadole 20 mg every 3–4 h Step 2c Peripheral analgesics plus adjuvant pharmaceuticals e.g. Step 2a plus tricyclic antidepressant or neuroleptics Step 3 Potent opioid e.g. Buprenorphine 400 g q.i.d. Step 4 Operation If pain control is incomplete, and in case of development of narcotics dependence

antioxidant treatment ameliorates pancreatic damage in pancreatitis models [27, 28]. Two studies reported beneﬁcial effects following treatments with antioxidant cocktails or micronutrients [29, 30]. Another study showed no beneﬁt using allopurinol for pain control [31]. Inhibition of gastric acid secretion is another hypothesis-driven treatment option. Elevation of duodenal pH is supposed to decrease pancreatic secretion. To date, no studies have been performed to investigate the role of gastric acid suppression on pain control in chronic pancreatitis. However, many centers use proton pump inhibitors regularly as a therapeutic means for pain control in patients with pancreatitis. A different way to decrease pancreatic secretion may be the use of the somatostatin analog octreotide. However, studies have shown conﬂicting results [32, 33]. In the setting of increasing abdominal pain, morphological examinations of the pancreas such as endoscopic retrograde pancreatocholangiography or CT are mandatory to exclude ductal, parenchymal or extrapancreatic complications which may be responsible for deterioration of abdominal pain, and which may require endoscopic or surgical intervention. Several interventional approaches exist for the treatment of pancreatic pain including endoscopic treatment, drainage operations, surgical resections and denervation procedures.

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The general goal of endoscopic therapy is to improve drainage of the pancreatic duct thereby decompressing the pancreatic duct and reducing abdominal pain. This goal can be achieved by endoscopic stent placement, stone extraction, dilatation of strictures and pancreatic sphincterotomy. However, the individual contribution of each of these modalities is impossible to determine since they are often performed together. A central issue is the selection of the patient for the procedure. Generally, patients with large duct disease and possible ductal hypertension may beneﬁt from endoscopic therapy. While there are no studies comparing medical and endoscopic therapy, a recent study found surgical therapy superior to endoscopy [34]. In patients with intractable abdominal pain not responding to medical therapy, surgical approaches have to be considered. Again, these interventions aim to relieve pancreatic pain by reducing ductal obstruction and pancreatic pressure. In addition, surgery remains necessary in patients presenting with complications that involve adjacent organs such as duodenal, splenic vein, or biliary duct obstruction. Other indications for surgery are pseudocysts that fail to respond to endoscopic therapy, internal pancreatic ﬁstulas, and the exclusion of expected malignancies that may develop during the course of the disease. Another approach in the treatment of intractable abdominal pain represent denervation procedures by celiac plexus blockade either by endoscopic ultrasound or in a CT-guided fashion. However, this therapy appears not to be very effective in patients with chronic pancreatitis [16, 35]. The main obstacle to treatment of pancreatitis pain is the relatively short period of pain relief with persistent beneﬁt in only 10% of patients after 24 weeks in a large study [35]. While this may be acceptable in end-stage malignant disease, it requires repeated procedures in patients with chronic pancreatitis. Therefore, celiac plexus blockade is applied rarely in patients with chronic pancreatitis.

Treatment of Exocrine Insufficiency

Supplementation of pancreatic enzymes is indicated in patients with pancreatic exocrine insufﬁciency. Pancreatic exocrine insufﬁciency occurs if more than 90% of the functional capacity of the gland is lost [36]. Clinically, maldigestion of fat caused by lipase deﬁciency leads to steatorrhea and malnutrition. Steatorrhea may be clinically apparent in about one third of the patients with

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chronic pancreatitis [37]. With sufﬁcient treatment, most patients can achieve satisfactory nutritional status and become relatively asymptomatic. First, patients should abstain from alcohol, should avoid large meals and should rather split their nutrient intake into 4–6 smaller meals/ day [38]. The diet should be rich in carbohydrates and proteins. However, the intake of carbohydrates has to be limited in the presence of endocrine insufﬁciency. If weight loss develops, or sufﬁcient weight gain is not achieved, medium chain triglycerides may be used to increase fat absorption [39]. Medium chain triglycerides are absorbed directly across the small bowel into the portal vein, even in the absence of lipase and bile salts. In addition, supplementation of fat-soluble vitamins and other micronutrients may be necessary [40–42]. Three types of enzyme replacement therapy are available: non-enteric coated formulations; enteric coated formulations, and microencapsulated enteric coated formulations. While in theory enteric coated preparations should be superior due to protection from acid-induced degradation of the enzymes in the stomach, most studies have failed to show large beneﬁts of these preparations [43–46]. If non-enteric preparations are used, gastric acid suppression may be necessary to increase the amount of functional enzyme reaching the duodenum [46]. While most studies have been performed using H2-receptor antagonists, today proton pump inhibitors may be the therapy of choice [47, 48].

Treatment of Endocrine Insufficiency

Endocrine insufﬁciency succeeds exocrine insufﬁciency in many patients, but can be the ﬁrst symptom of chronic pancreatitis in individual patients. It is important to understand that pancreatic diabetes represents a lack of insulin – comparable to type-1 diabetes – and therefore requires insulin treatment as well as diet. Since glucagon secretion is also impaired in chronic pancreatitis due to destruction of -cells in the islets of Langerhans, regulation of blood glucose levels can be severely impaired resulting in prolonged phases of hypoglycemia [49, 50]. Other factors contributing to the difﬁculties in maintaining adequate blood glucose levels are malnutrition or infrequent and irregular caloric intake due to alcohol abuse. Therefore insulin-induced hypoglycemic reactions represent serious complications and often remain difﬁcult to prevent [51]. As a consequence, mean blood glucose levels should not be normoglycemic, but should rather aim at levels between 120 and 150 mg/dl.

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In addition, the patient must be advised to take pancreatic enzymes with each meal to avoid absorption irregularities. The need for surgery may leave patients with brittle diabetes after the procedure; therefore patients should be

advised about this possible consequence of the therapy. However, in a prospective study, endocrine function was comparable in patients going to surgery compared with those having ongoing endoscopic therapy [34].

References 1 Talamini G, Bassi C, Falconi M, Frulloni L, Di Francesco V, Vaona B, et al: Cigarette smoking: an independent risk factor in alcoholic pancreatitis. Pancreas 1996;12:131–137. 2 Bourliere M, Barthet M, Berthezene P, Durbec JP, Sarles H: Is tobacco a risk factor for chronic pancreatitis and alcoholic cirrhosis? Gut 1991;32:1392–1395. 3 Lowenfels AB, Zwemer FL, Jhangiani S, Pitchumoni CS: Pancreatitis in a native American Indian population. Pancreas 1987;2:694–697. 4 Gullo L, Barbara L, Labo G: Effect of cessation of alcohol use on the course of pancreatic dysfunction in alcoholic pancreatitis. Gastroenterology 1988;95:1063–1068. 5 Maisonneuve P, Lowenfels AB, Mullhaupt B, Cavallini G, Lankisch PG, Andersen JR, et al: Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005; 54: 510–514. 6 de las Heras G, de la Pena J, Lopez Arias MJ, Gonzalez-Bernal AC, Martin-Ramos L, PonsRomero F: Drinking habits and pain in chronic pancreatitis. J Clin Gastroenterol 1995; 20: 33–36. 7 Strum WB: Abstinence in alcoholic chronic pancreatitis. Effect on pain and outcome. J Clin Gastroenterol 1995;20:37–41. 8 Miyake H, Harada H, Kunichika K, Ochi K, Kimura I: Clinical course and prognosis of chronic pancreatitis. Pancreas 1987; 2: 378– 385. 9 Moreau J, Bouisson M, Balas D, Ravaud A, Stupnik S, Buscail L, et al: Gastric lipase in alcoholic pancreatitis. Comparison of secretive proﬁles following pentagastrin stimulation in normal adults and patients with pancreatic insufﬁciency. Gastroenterology 1990; 99: 175– 180. 10 Hymowitz N, Cummings KM, Hyland A, Lynn WR, Pechacek TF, Hartwell TD: Predictors of smoking cessation in a cohort of adult smokers followed for ﬁve years. Tob Control 1997;6(suppl 2):S57–S62. 11 Hays JT, Schroeder DR, Offord KP, Croghan IT, Patten CA, Hurt RD, et al: Response to nicotine dependence treatment in smokers with current and past alcohol problems. Ann Behav Med 1999;21:244–250. 12 Bockman DE, Buchler M, Malfertheiner P, Beger HG: Analysis of nerves in chronic pancreatitis. Gastroenterology 1988;94:1459–1469. 13 Bradley EL 3rd: Pancreatic duct pressure in chronic pancreatitis. Am J Surg 1982; 144: 313–316.

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14 Patel AG, Toyama MT, Alvarez C, Nguyen TN, Reber PU, Ashley SW, et al: Pancreatic interstitial pH in human and feline chronic pancreatitis. Gastroenterology 1995; 109: 1639–1645. 15 Mössner J, Keim V, Niederau C, Buchler M, Singer MV, Lankisch PG, et al: Guidelines for therapy of chronic pancreatitis. Consensus Conference of the German Society of Digestive and Metabolic Diseases. Halle 21–23 November 1996 (in German). Z Gastroenterol 1998; 36:359–367. 16 Apte MV, Wilson JS: Alcohol-induced pancreatic injury. Best Pract Res Clin Gastroenterol 2003;17:593–612. 17 Thompson DR: Narcotic analgesic effects on the sphincter of Oddi: a review of the data and therapeutic implications in treating pancreatitis. Am J Gastroenterol 2001;96:1266–1272. 18 Wu SD, Zhang ZH, Jin JZ, Kong J, Wang W, Zhang Q, et al: Effects of narcotic analgesic drugs on human Oddi’s sphincter motility. World J Gastroenterol 2004;10:2901–2904. 19 Cuer JC, Dapoigny M, Ajmi S, Larpent JL, Lunaud B, Ferrier C, et al: Effects of buprenorphine on motor activity of the sphincter of Oddi in man. Eur J Clin Pharmacol 1989; 36: 203–204. 20 Slaff J, Jacobson D, Tillman CR, Curington C, Toskes P: Protease-speciﬁc suppression of pancreatic exocrine secretion. Gastroenterology 1984;87:44–52. 21 Isaksson G, Ihse I: Pain reduction by an oral pancreatic enzyme preparation in chronic pancreatitis. Dig Dis Sci 1983;28:97–102. 22 Halgreen H, Pedersen NT, Worning H: Symptomatic effect of pancreatic enzyme therapy in patients with chronic pancreatitis. Scand J Gastroenterol 1986;21:104–108. 23 Larvin M, McMahon MJ, Thomas WEG, Puntis MCA: Creon (enteric coated pancreatin microspheres) for the treatment of pain in chronic pancreatitis: a double-blind randomised placebo-controlled crossover study. Gastroenterology 1991;100:A283. 24 Mössner J, Secknus R, Meyer J, Niederau C, Adler G: Treatment of pain with pancreatic extracts in chronic pancreatitis: results of a prospective placebo-controlled multicenter trial. Digestion 1992;53:54–66.

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25 Malesci A, Gaia E, Fioretta A, Bocchia P, Ciravegna G, Cantor P, et al: No effect of longterm treatment with pancreatic extract on recurrent abdominal pain in patients with chronic pancreatitis. Scand J Gastroenterol 1995;30:392–398. 26 American Gastroenterological Association Medical Position Statement: treatment of pain in chronic pancreatitis. Gastroenterology 1998;115:763–764. 27 Virlos I, Mazzon E, Serraino I, Genovese T, Di Paola R, Thiemerman C, et al: Calpain I inhibitor ameliorates the indices of disease severity in a murine model of cerulein-induced acute pancreatitis. Intensive Care Med 2004; 30:1645–1651. 28 Yoo BM, Oh TY, Kim YB, Yeo M, Lee JS, Surh YJ, et al: Novel antioxidant ameliorates the ﬁbrosis and inﬂammation of cerulein-induced chronic pancreatitis in a mouse model. Pancreatology 2005;5:165–176. 29 De las Heras Castano G, Garcia de la Paz A, Fernandez MD, Fernandez Forcelledo JL: Use of antioxidants to treat pain in chronic pancreatitis. Rev Esp Enferm Dig 2000;92:375–385. 30 Uden S, Bilton D, Nathan L, Hunt LP, Main C, Braganza JM: Antioxidant therapy for recurrent pancreatitis: placebo-controlled trial. Aliment Pharmacol Ther 1990;4:357–371. 31 Banks PA, Hughes M, Ferrante M, Noordhoek EC, Ramagopal V, Slivka A: Does allopurinol reduce pain of chronic pancreatitis? Int J Pancreatol 1997;22:171–176. 32 Toskes PP, Forsmark CE, De Meo M, et al: A multi-center controlled trial of octreotide for the pain of chronic pancreatitis (abstract). Pancreas 1993;8:774. 33 Malfertheiner P, Mayer D, Buchler M, Dominguez-Munoz JE, Schiefer B, Ditschuneit H: Treatment of pain in chronic pancreatitis by inhibition of pancreatic secretion with octreotide. Gut 1995;36:450–454. 34 Dite P, Ruzicka M, Zboril V, Novotny I: A prospective, randomized trial comparing endoscopic and surgical therapy for chronic pancreatitis. Endoscopy 2003;35:553–558. 35 Gress F, Schmitt C, Sherman S, Ciaccia D, Ikenberry S, Lehman G: Endoscopic ultrasound-guided celiac plexus block for managing abdominal pain associated with chronic pancreatitis: a prospective single center experience. Am J Gastroenterol 2001;96:409–416.

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36 DiMagno EP, Go VL, Summerskill WH: Relations between pancreatic enzyme ouputs and malabsorption in severe pancreatic insufﬁciency. N Engl J Med 1973;288:813–815. 37 Lankisch PG, Droge M, Hofses S, Konig H, Lembcke B: Steatorrhoea: you cannot trust your eyes when it comes to diagnosis. Lancet 1996;347:1620–1621. 38 Meier R: Nutrition in chronic pancreatitis; in Büchler MW, Friess H, Uhl W, Malfertheiner P (eds): Chronic Pancreatitis. Berlin, Blackwell Wissenschafts-Verlag, 2002, pp 420–427. 39 Perry RS, Gallagher J: Management of maldigestion associated with pancreatic insufﬁciency. Clin Pharm 1985;4:161–169. 40 Dutta SK, Bustin MP, Russell RM, Costa BS: Deﬁciency of fat-soluble vitamins in treated patients with pancreatic insufﬁciency. Ann Intern Med 1982;97:549–552. 41 Marotta F, Labadarios D, Frazer L, Girdwood A, Marks IN: Fat-soluble vitamin concentration in chronic alcohol-induced pancreatitis. Relationship with steatorrhea. Dig Dis Sci 1994;39:993–998.

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42 Nakamura T, Takebe K, Imamura K, Tando Y, Yamada N, Arai Y, et al: Fat-soluble vitamins in patients with chronic pancreatitis (pancreatic insufﬁciency). Acta Gastroenterol Belg 1996;59:10–14. 43 Gouerou H, Dain MP, Parrondo I, Poisson D, Bernades P: Alipase versus nonenteric-coated enzymes in pancreatic insufﬁciency. A French multicenter crossover comparative study. Int J Pancreatol 1989;5(suppl):45–50. 44 Dutta SK, Rubin J, Harvey J: Comparative evaluation of the therapeutic efﬁcacy of a pHsensitive enteric coated pancreatic enzyme preparation with conventional pancreatic enzyme therapy in the treatment of exocrine pancreatic insufﬁciency. Gastroenterology 1983; 84:476–482. 45 Graham DY: An enteric-coated pancreatic enzyme preparation that works. Dig Dis Sci 1979; 24:906–909.

46 Regan PT, Malagelada JR, DiMagno EP, Glanzman SL, Go VL: Comparative effects of antacids, cimetidine and enteric coating on the therapeutic response to oral enzymes in severe pancreatic insufﬁciency. N Engl J Med 1977; 297:854–858. 47 Bruno MJ, Rauws EA, Hoek FJ, Tytgat GN: Comparative effects of adjuvant cimetidine and omeprazole during pancreatic enzyme replacement therapy. Dig Dis Sci 1994;39:988– 992. 48 Nakamura T, Arai Y, Tando Y, Terada A, Yamada N, Tsujino M, et al: Effect of omeprazole on changes in gastric and upper small intestine pH levels in patients with chronic pancreatitis. Clin Ther 1995;17:448–459. 49 Bank S, Marks IN, Vinik AI: Clinical and hormonal aspects of pancreatic diabetes. Am J Gastroenterol 1975;64:13–22. 50 Sjoberg RJ, Kidd GS: Pancreatic diabetes mellitus. Diabetes Care 1989;12:715–724. 51 Linde J, Nilsson LH, Barany FR: Diabetes and hypoglycemia in chronic pancreatitis. Scand J Gastroenterol 1977;12:369–373.

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dence including the insights into complex trait genetics. The process leading from a normal pancreas to end-stage chronic pancreatitis has been organized into a conceptual model, the Sentinel Acute Pancreatitis Event (SAPE) hypothesis model [7], with various risk factors organized into steps and domains [8]. The SAPE hypothesis model allows the role of alcohol, environmental factors (e.g. tobacco smoking), genetic factors and the immunological response to pancreatic injury to be considered in an organized way so that the speciﬁc factors leading to alcoholic chronic pancreatitis can be considered.

Pathophysiology of Chronic Pancreatitis

Chronic pancreatitis is a pathologic diagnosis. The diagnosis is based on the histological appearance of the pancreas at the end of an inﬂammatory process associated with extensive ﬁbrosis, beginning with a variety of proximal etiologies, including alcohol. The proximal etiology, especially the role of alcohol, has been obscure because in systematic sampling of pancreatic tissue from alcoholics or others a risk of pancreatitis was impossible, and early animal models of heavy alcohol consumption did not develop chronic pancreatitis (as in most humans with heavy alcohol consumption). One of the major breakthroughs in understanding chronic pancreatitis came with discovery that the mutations in the cationic trypsinogen gene (PRSS1) were associated with recurrent acute and chronic pancreatitis [9, 10]. This ﬁnding indicated that in humans the proximal event was unregulated trypsin activity within the pancreas, followed by an inﬂammatory response. Subsequent genetic studies in the pancreatic secretory trypsin inhibitor gene (SPINK1) [11, 12] and the cystic ﬁbrosis transmembrane conductance regulator gene (CFTR) [13, 14] also suggest that failure to inhibit trypsin or to quickly ﬂush trypsin from the pancreatic duct is also associated with recurrent acute and chronic pancreatitis. These studies, and other lines of evidence [for reviews, see 7, 15] provide compelling evidence that recurrent acute pancreatitis precedes chronic pancreatitis. Although this does not prove the proximal cause in alcoholic chronic pancreatitis, it helps break up the process into steps of recurrent injury and several types of immunological responses (including ﬁbrosis). The SAPE hypothesis model was developed by the author in 1999 as a framework for understanding the relationship between risk factors, acute pancreatitis, and recurrent acute pancreatitis in the process of developing

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chronic pancreatitis – with special attention to the immune system [16]. The model is important in considering why many individuals who are exposed to important risk factors, such as large amounts of alcohol, do not develop chronic pancreatitis. Since chronic pancreatitis is an immune-mediated event, there must be a signiﬁcant event to activate the immune system speciﬁcally within the pancreas and to initiate the inﬂammatory process. This event was hypothesized to be an episode of acute pancreatitis (called the sentinel event) because it foresees the potential development of chronic pancreatitis. The SAPE hypothesis model differs from the necrosis-ﬁbrosis hypothesis in that pancreatic necrosis is not necessary, and the basis for the extensive ﬁbrosis without clinically recognized severe acute pancreatitis is explained. The SAPE hypothesis model also allows us to consider factors that increase the risk for acute pancreatitis, independent of the factors that drive ﬁbrosis through their effects on the immune system. Furthermore, the various types of immune responses and cellular components can also be studied (e.g. macrophages, pancreatic stellate cells) as components of an integrated process. Overall, the SAPE hypothesis model allows both environmental and genetic risk factors to be considered in terms of speciﬁc sites of action and as to their contribution to the overall process.

Alcohol as a Risk Factor for Acute and Chronic Pancreatitis

Early attempts to understand the relationship between alcohol and chronic pancreatitis were based on the assumption that alcohol was a pancreatic toxin and that if a threshold amount was exceeded, ﬁbrosis would ensue with a dose-response relationship between the amount of alcohol and the severity of ﬁbrosis. Indeed, in large populations such a relationship can be constructed in the subset of patients who develop chronic pancreatitis [3]. Patients with excess alcohol consumption but without pancreatitis were ignored, while those who develop chronic pancreatitis without a sufﬁcient alcohol history are considered surreptitious alcoholics or idiopathic chronic pancreatitis patients [4]. The best evidence that there is a dose-response relationship between alcohol consumption and chronic pancreatitis comes from South Africa where Durbec and Sarles [17] demonstrated that the risk of chronic pancreatitis was a log function of alcohol consumption in a deﬁned population. In this and other studies it was suggested that

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for chronic pancreatitis the amount of alcohol that needed to be consumed was 180 g/day for many years [3, 17– 19]. The process also appears to be a prolonged one, with the interval between the start of continuous alcohol abuse and the typical clinical manifestation of alcohol-induced chronic pancreatitis presenting with tissue ﬁbrosis and pancreaticolithiasis requires 15–20 years [2, 20]. On the other hand, most alcoholics do not develop chronic pancreatitis. Compared to other alcohol-related injuries the association between alcohol intake and chronic pancreatitis is weak [21]. Furthermore, the 80-g/day ‘threshold’ may not be very ﬁrm since there is clearly an increased risk for patients who drinking less than two drinks or two glasses of wine (25 g) per day [17, 22]. Finally, clinically relevant pancreatic disease occurs in less than 5% of heavy alcohol drinkers [23]. These observations demonstrate marked heterogeneity in the susceptibility of humans to chronic alcoholic pancreatitis. Therefore, it appears that alcohol is a cofactor in the development of alcoholic pancreatitis in ‘susceptible’ humans. The other cofactors are yet to be determined, but could be environmental or genetic. Animal studies have been useful in providing a number of insights into human alcoholic chronic pancreatitis. Long-term feeding of alcohol to rats does not cause chronic pancreatitis [24–27] but it does lead to dose-dependent changes in physiology [24], including the effects of ongoing oxidative stress [28] and chronic mitochondrial damage [29]. These effects of alcohol do not drive ﬁbrosis, but they do appear to lower the threshold for hyperstimulation-induced trypsin activation and acute pancreatic injury [27, 30, 31]. Therefore, in animals, chronic alcohol consumption is a susceptibility factor for acute pancreatitis, but pancreatitis only occurs following pancreatic hyperstimulation which triggers each individual episode. Alcohol may also increase susceptibility to acute pancreatitis by causing functional hyperstimulation, a complex process that is associated with physiological changes in the brainstem and acinar cell that result in an exaggerated response to a given neurohormonal stimulant [24, 32]. Thus, alcohol has the double susceptibility effect lowering the threshold for pancreatitis with a given amount of stimulation and increasing the amount of pancreatic stimulation with a given stimulant. This combined effect may be greatest immediately after withdrawal of chronic alcohol plus feeding [24]. Together, these studies provide insight into the context of heightened susceptibility to human alcoholic acute pancreatitis. Genetic factors could potentiate both the susceptibility and frequency of alcoholic acute pancreatitis.

Animal studies also provide insight into the effects of alcohol on the immune system, which is responsible for destruction of normal acinar cells and for driving ﬁbrosis through the stellate cells. Alcohol itself usually behaves as an anti-inﬂammatory agent [32]. This concept is important since anti-inﬂammatory factors (e.g. TGF-) appears to drive ﬁbrosis [33]. We tested the effect of alcohol on rats given multiple episodes of acute pancreatitis to test the role of alcohol using the SAPE hypothesis model [34]. These studies outlined the time course of the inﬂammatory and other key responses to one and three episodes of hyperstimulation (cerulean-induced) acute pancreatitis and demonstrate a marked effect of alcohol in this model. In animals with repeated acute pancreatitis plus continued alcohol exposure there was marked upregulation of proinﬂammatory cytokines including MCP-1, MIP-1, RANTES and IL-12 plus the anti-inﬂammatory TGF- and IL-10 [34]. The anti-inﬂammatory cytokine response, inﬂammatory cell inﬁltrate, stellate cell activation, and markers of ﬁbrosis were markedly elevated only in rats with recurrent acute pancreatitis plus continued alcohol [34]. Most striking were the increases in procollagen-2, collagen-1 and ﬁbronectin mRNA, pancreatic hydroxyproline levels, and activation of pancreatic stellate cells (-SMA staining) and ﬁbrosis (Sirius red stain) [34] seen in alcohol-fed rats with multiple episodes of acute pancreatitis. In other studies alcohol also appears to have a direct effect on the pancreatic stellate cells [35, 36]. These results suggest that alcohol alters the immune response to recurrent acute pancreatitis to promote ﬁbrosis – the hallmark of chronic pancreatitis. These animal studies indicate that alcohol does not cause chronic pancreatitis directly, but facilitates hyperstimulation, lowers the threshold for acute pancreatitis, and promotes ﬁbrosis. The fact that alcohol acts at multiple steps in the process leading to chronic pancreatitis increases the probability that alcoholic patients will develop chronic pancreatitis compared to patients with risk factors that act at a single step in the process. However, patients with multiple risk factors will likely have increased susceptibility and accelerated process to endstage ﬁbrosis.

Genetics of Alcoholic Pancreatitis

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Genetic and Environmental Risk Factors in Alcoholic Chronic Pancreatitis

If alcohol is not sufﬁcient to cause chronic pancreatitis, then what are the other factors that further increase the risk of acute pancreatitis or ﬁbrosis? Based on the discus-

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sion above, there will likely be separate factors that increase susceptibility and alter the immune response to recurrent injury. Susceptibility Genes Several genetic factors have been identiﬁed that increase susceptibility to pancreatitis independent of alcohol, but that might markedly increase susceptibility in the presence of alcohol. The major pancreatitis susceptibility factors include variations in the cationic trypsinogen gene (PRSS1) [9, 10], the pancreatic secretory trypsin inhibitor gene (SPINK1) [11, 12] and the cystic ﬁbrosis transmembrane conductance regulator gene (CFTR) [13, 14]. The possibility that these genes play a role in alcoholic pancreatitis has been investigated. Teich et al. [37] tested 23 alcoholic pancreatitis patients for mutations in the cationic trypsinogen mutations. Cationic trypsinogen mutations (R122H or N291) were not found to be predisposing factors in patients with chronic and recurrent acute alcoholic pancreatitis [37]. Creighton et al. [38] screened 133 patients with pancreatitis of different origins including an undeﬁned number of patients with alcoholic pancreatitis. No cationic trypsinogen mutations were found. Monaghan et al. [39] performed a sequence analysis of the cationic trypsinogencoding region in 46 patients without ﬁnding any cationic trypsinogen gene mutations. Truninger et al. [40] screened 58 patients with alcoholic pancreatitis for cationic trypsinogen mutations. No mutations of exon 2 (N29I) or exon 3 (R122H) were found. These data exclude hereditary pancreatitis-associated trypsinogen mutations as a major cofactor for alcoholic pancreatitis. The pancreatic secretory trypsin inhibitor (SPINK1) inhibits prematurely activated trypsinogen within the pancreas [9, 11]. SPINK1 speciﬁcally inhibits trypsin by competitively blocking the active site of the molecule [41]. Although SPINK1 mutations are very common in early-onset idiopathic chronic pancreatitis [11], familial pancreatitis [12] and tropical pancreatitis [42, 43] and are seen in up to 3% of patients in the general population [44], SPINK1 mutations are only seen in a minority of patients with alcoholic pancreatitis. Several groups investigated the frequency of the SPINK1 N34S mutation in alcoholics from Europe [11, 45, 46]. The N34S mutation was detected in 5.8% of patients (n = 16/274) with alcoholic pancreatitis and in 0.8% of the control population (n = 4/540) [11]. Although the frequency was only slightly elevated in patients compared to controls, the difference was statistically signiﬁcant. More recently, two other studies from Europe reported similar frequencies in

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patients with alcoholic chronic pancreatitis [45, 46]. Schneider et al. [47] found similar small, but statistically signiﬁcant association between SPINK1 N34S mutations and alcoholic pancreatitis. The relatively low frequency of N34S mutations in patients with alcoholic chronic pancreatitis suggests that this genetic variant does not play an important role in the majority of patients. However, the relationship between the intrapancreatic serine proteases and the inhibitor is complex, and several features of this relationship may be of relevance in some individuals with alcoholic chronic pancreatitis. The CFTR gene contains over 4,300 nucleotides, divided into 24 exons which code for a single protein of 1,480 amino acids. Over 1,250 polymorphisms have been reported, and many of these polymorphisms are very common in human populations. Screening the entire gene by DNA sequencing or other techniques are very expensive and difﬁcult. Thus, most of the studies focused on only a few common mutations that are know to be associated with cystic ﬁbrosis. Several groups screened the CFTR delF508 gene and a few other variants in patients with chronic alcoholic pancreatitis. Malats et al. [48] investigated whether or not the severe CFTR mutation F508 or the common mild mutation of the ‘5T allele’ were associated in patients from Spain. There was no association found. A second study from Southern Europe also found no correlation between alcoholic pancreatitis and CFTR mutations [49]. Norton et al. [50] screened for 15 mutations including the F508 mutation but did not ﬁnd any association between CFTR mutations and the individual susceptibility to alcoholic chronic pancreatitis in white Australians. Haber et al. [51], in a study by the same group, also screened alcoholic patients in Australia for the 5T allele and found no association with alcoholic pancreatitis. Finally, Monaghan et al. [39] screened for 40 cystic ﬁbrosis mutations including the 5T allele in 46 alcohol-related pancreatitis patients. In contrast to the ﬁndings published by Malats et al. [48], an excess prevalence of the F508 mutation was identiﬁed in white (but not in African-American) alcoholic chronic pancreatitis patients compared to healthy controls [39]. In conclusion, initial studies looking at a limited number of CFTR polymorphisms failed to identify an association with alcohol consumption and pancreatitis. However, these studies are inadequate to fully test the hypothesis that a subset of CFTR mutations represents a signiﬁcant genetic risk factor for alcohol-associated pancreatic injury.

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Alcohol-Metabolizing and Detoxifying Genes The three susceptibility genes discussed above speciﬁcally address the problem of controlling trypsinogen activation, trypsin inhibition, and trypsin ﬂushing from the pancreatic duct. Increased susceptibility to alcoholic pancreatitis could also be affected by factors associated with neurohormonal control of stimulation, or intracinar cell stress that make the acinar cell more sensitive to trypsinogen activation with stimulation. Alcohol-metabolizing enzymes such as alcohol dehydrogenase (ADH) exist as different isoenzymes and are known to be involved in the detoxiﬁcation of ethanol. This detoxiﬁcation process occurs in the cytosol of acinar cells and results in the production of acetaldehyde as shown by Haber et al. [52]. Couzigou et al. [53] and Haber et al. [52] suggested that high- or low-activity phenotypes of ADH phenotypes may inﬂuence the metabolism of ethanol in pancreatitis and increase the susceptibility to alcohol-induced cell damage. Two small studies from Day et al. [54] and Dumas et al. [55] showed an increased frequency of the ADH-3 (ADH3)*1 gene (encoding the high activity of the 1-ADH isoenzyme), but the number of patients was too small to be signiﬁcant. When pooling the data of the above-mentioned studies there was a trend toward an increased prevalence of the 1-ADH isoenzyme in patients with alcoholic chronic pancreatitis [56]. A study from Taiwan published by Chao et al. [57] hypothesized later on that there might be an association between the ADH2*2 gene and (acute) alcoholic pancreatitis. However, the data published for patients with chronic alcoholic pancreatitis are not conclusive: No correlation was found between ADH2 polymorphisms and chronic pancreatitis in Japanese patients by Kimura et al. [58], and in 71 Australian patients (of European origin) by Frenzer et al. [59], while an elevated risk for chronic alcoholic pancreatitis for different genotypes of ADH2 was demonstrated by Maruyama et al. [60]. In conclusion, further studies are needed to clarify these discrepancies, but these polymorphisms do not appear to be the key cofactors for alcoholic pancreatitis. Cytochrome P450 is involved in the second important enzymatic pathway known to metabolize ethanol to acetaldehyde. In contrast to the ADH pathway this pathway is localized within the cellular endoplasmatic reticulum. Known polymorphisms of cytochrome P450IIE1 (CYP2E1) were investigated by Yang et al. [61], Chao et al. [62], and Frenzer et al. [59], who found no association between polymorphisms of this gene and alcoholic chronic pancreatitis.

Polymorphisms of other enzymes potentially involved in free radical stress and acinar cell damage [63], such as enzymes of the glutathione S-transferase (GST) family, were investigated for a potential association with an increased susceptibility to pancreatic disorders [64]. While Bartsch et al. [65] suggested a moderate increase in susceptibility to pancreatitis due to polymorphisms of GSTM1, this association was not conﬁrmed by Frenzer et al. [59] and Schneider et al. [66]. Rahman et al. [67] recently published a paper claiming that the GSTT1 null genotypes were protective against severe acute alcoholic pancreatitis. This study has not been reproduced in other populations and appears to be related to acute rather than chronic pancreatitis. Contradictory results have been reported regarding an association of polymorphisms of the detoxifying enzyme aldehyde dehydrogenase-1 (ALDH2) and alcoholic pancreatitis. While Kimura et al. [58] concluded that genetic polymorphisms of the ALDH2 gene inﬂuence the risk of developing alcoholic pancreatitis (in Japanese patients), this was not conﬁrmed by Maruyama et al. [60] in Japanese and by Frenzer et al. [59] in Caucasian patients. UDP glucuronosyltransferase (UGT1A7) gene polymorphisms were recently reported to increase the risk of chronic pancreatitis in alcoholics [68]. The interesting observation is that this is a xenobiotic detoxifying enzyme that is important in metabolizing components of tobacco smoke rather than metabolizing alcohol. Since there was a high association of tobacco smoking in European alcoholics [68], it is impossible to determine if this gene is associated with the tobacco or alcohol. There was no association with polymorphisms in similar UDP gene subtypes, 1A1, 1A6 or 1A8 [69].

Genetics of Alcoholic Pancreatitis

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Immune Response Genes The development of chronic pancreatitis is multidimensional and includes an altered immune response [8]. Among the ﬁrst immune-associated genetic factors to be considered were HLA antigens. Although several HLA antigens have been found to be correlated with alcoholic chronic pancreatitis, most studies suffered from a poor study design by using nonalcoholic controls and thus could not differentiate between the effects of alcoholism per se and those of alcoholic pancreatitis [70–72]. The reason for the striking differences in the published HLA patterns are unknown, but might be explained by ethnic differences between the countries [73]. Wilson et al. [73] showed an increased incidence of HLA Bw 39 in pancreatitis which was related to alcoholic pancreatitis rather than to alcoholism itself, but this ﬁnding fails to explain

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most cases of alcohol-associated pancreatitis. There are many other genetic risk factors related to the immunological response that could play a role in alcoholic pancreatitis. However, little information has been published. One of the most important cofactors in the development of chronic pancreatitis is tobacco smoking [74–77]. Tobacco smoking differs from alcoholism in that it does not appear to increase susceptibility to acute pancreatitis, but rather drives ﬁbrosis once the immune system has been activated (according to the SAPE hypothesis model). Interestingly, one of the major factors driving ﬁbrosis in tobacco smoke may be carbon monoxide [78, 79]. Further work in this area is also needed.

Conclusion

Although alcohol consumption remains a major factor associated with acute and chronic pancreatitis, alcohol alone does not cause acute or chronic pancreatitis. Growing evidence suggests that genetic or environmental cofactors are required, but this factor remains illusive. On the other hand, some genetic polymorphisms, such as those in SPINK1 and perhaps CFTR or others, do appear to increase the risk of pancreatitis. However, the dominant cofactor(s) remains to be determined.

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11 Witt H, Luck W, Hennies HC, Classen M, Kage A, Lass U, et al: Mutations in the gene encoding the serine protease inhibitor, Kazal type 1 are associated with chronic pancreatitis. Nat Genet 2000;25:213–216. 12 Pfützer RH, Barmada MM, Brunskil APJ, Finch R, Hart PS, Neoptolemos J, et al: SPINK1/PSTI polymorphisms act as disease modiﬁers in familial and idiopathic chronic pancreatitis. Gastroenterology 2000;119:615– 623. 13 Sharer N, Schwarz M, Malone G, Howarth A, Painter J, Super M, et al: Mutations of the cystic ﬁbrosis gene in patients with chronic pancreatitis. N Engl J Med 1998;339:645–652. 14 Cohn JA, Friedman KJ, Noone PG, Knowles MR, Silverman LM, Jowell PS: Relation between mutations of the cystic ﬁbrosis gene and idiopathic pancreatitis. N Engl J Med 1998; 339:653–658. 15 Whitcomb DC. Gene mutations as a cause of chronic pancreatitis; in Adler G, Ammann R, Buchler M, DiMagno EP, Sarner M (eds): Pancreatitis: Advances in Pathobiology, Diagnosis and Treatment (Falk Symposium 143). Lancaster, Springer, 2005. 16 Whitcomb DC: Hereditary pancreatitis: new insights into acute and chronic pancreatitis. Gut 1999;45:317–322. 17 Durbec J, Sarles H: Multicenter survey of the etiology of pancreatic diseases. Relationship between the relative risk of developing chronic pancreatitis and alcohol, protein and lipid consumption. Digestion 1978;18:337–350. 18 Marks IN, Bank S: The etiology, clinical features and diagnosis of pancreatitis in the South Western Cape: a review of 243 cases. S Afr Med J 1963;37:1039–1053. 19 Ammann RW, Heitz PU, Kloppel G: Alcoholic pancreatitis: from what histological starting point? Gastroenterology 1997;112:1429.

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29 Li HS, Zhang JY, Thompson BS, Deng XY, Ford ME, Wood PG, et al: Rat mitochondrial ATP synthase ATP5G3:cloning and upregulation in pancreas after chronic ethanol feeding. Physiol Genomics 2001;6:91–98. 30 Gorelick FS: Alcohol and zymogen activation in the pancreatic acinar cell. Pancreas 2003;24: 305–310. 31 Katz M, Carangelo R, Miller LJ, Gorelick F: Effect of ethanol on cholecystokinin-stimulated zymogen conversion in pancreatic acinar cells. Am J Physiol 1996;270:G171–G175. 32 Deng X, Wood PG, Eagon PK, Whitcomb DC: Rapid adaptation of pancreatic exocrine function to short term alcohol feeding in rats. Pancreatology 2005;5:183–195. 33 Van Laethem J, Robberecht P, Resibois A, Deviere J: Transforming growth factor beta promotes development of ﬁbrosis after repeated courses of acute pancreatitis in mice. Gastroenterology 1996;110:576–582. 34 Deng X, Wang L, Elm MS, Gabazadeh D, Diorio GJ, Eagon PK, et al: Chronic alcohol consumption accelerates ﬁbrosis in response to cerulein-induced pancreatitis in rats. Am J Pathol 2005;166:93–106. 35 Apte MV, Phillips PA, Fahmy RG, Darby SJ, Rodgers SC, McCaughan GW, et al: Does alcohol directly stimulate pancreatic ﬁbrogenesis? Studies with rat pancreatic stellate cells. Gastroenterology 2000;118:780–794. 36 Apte MV, Wilson JS: Stellate cell activation in alcoholic pancreatitis. Pancreas 2003;27:316– 320. 37 Teich N, Mossner J, Keim V: Screening for mutations of the cationic trypsinogen gene: are they of relevance in chronic alcoholic pancreatitis? Gut 1999;44:413–416. 38 Creighton J, Lyall R, Wilson DI, Curtis A, Charnley R: Mutations of the cationic trypsinogen gene in patients with chronic pancreatitis. Lancet 1999;354:42–43. 39 Monaghan KG, Jackson CE, KuKuruga DL, Feldman GL: Mutation analysis of the cystic ﬁbrosis and cationic trypsinogen genes in patients with alcohol-related pancreatitis. Am J Med Genet 2000;94:120–124. 40 Truninger K, Malik N, Ammann RW, Muellhaupt B, Seifert B, Muller HJ, et al: Mutations of the cystic ﬁbrosis gene in patients with chronic pancreatitis. Am J Gastroenterol 2001; 96:2657–2661. 41 Rinderknecht H: Activation of pancreatic zymogens. Normal activation, premature intrapancreatic activation, protective mechanisms against inappropriate activation. Dig Dis Sci 1986;31:314–321. 42 Rossi L, Pfützer RL, Parvin S, Ali L, Sattar S, Azad Kahn AK, et al: SPINK1/PSTI mutations are associated with tropical pancreatitis in Bangladesh: a preliminary report. Pancreatology 2001;1:242–245.

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43 Chandak GR, Idris MM, Reddy DN, Bhaskar S, Sriram PV, Singh L: Mutations in the pancreatic secretory trypsin inhibitor gene (PSTI/ SPINK1) rather than the cationic trypsinogen gene (PRSS1) are signiﬁcantly associated with tropical calciﬁc pancreatitis. J Med Genet 2002;39:347–351. 44 Whitcomb DC: How to think about SPINK and pancreatitis. Am J Gastroenterol 2002;97: 1085–1088. 45 Threadgold J, Greenhalf W, Ellis I, Howes N, Lerch MM, Simon P, et al: The N34S mutation of SPINK1 (PSTI) is associated with a familial pattern of idiopathic chronic pancreatitis but does not cause the disease. Gut 2002;50:675– 681. 46 Drenth JP, te Morsche R, Jansen JB: Mutations in serine protease inhibitor Kazal type 1 are strongly associated with chronic pancreatitis. Gut 2002;50:687–692. 47 Schneider A, Pfützer RH, Barmada MM, Slivka A, Martin J, Whitcomb DC: Limited contribution of the SPINK1 N34S mutation to the risk and severity of alcoholic chronic pancreatitis – a preliminary report from the United States. Dig Dis Sci 2003;48:1110–1115. 48 Malats N, Casals T, Porta M, Guarner L, Estivill X, Real FX: Cystic ﬁbrosis transmembrane regulator (CFTR) DeltaF508 mutation and 5T allele in patients with chronic pancreatitis and exocrine pancreatic cancer. PANKRAS II Study Group. Gut 2001;48:70–74. 49 Gaia E, Salacone P, Gallo M, Promis GG, Brusco A, Bancone C, Carlo A: Germline mutations in CFTR and PSTI genes in chronic pancreatitis patients. Dig Dis Sci 2002; 47: 2416–2421. 50 Norton ID, Apte MV, Dixson H, Trent RJ, Haber PS, Pirola RC, et al: Cystic ﬁbrosis genotypes and alcoholic pancreatitis. J Gastroenterol Hepatol 1998;13:496–499. 51 Haber PS, Norris MD, Apte MV, Rodgers SC, Norton ID, Pirola RC, et al: Alcoholic pancreatitis and polymorphisms of the variable length polythymidine tract in the cystic ﬁbrosis gene. Alcohol Clin Exp Res 1999;23:509–512. 52 Haber PS, Apte MV, Applegate TL, Norton ID, Korsten MA, Pirola RC, et al: Metabolism of ethanol by rat pancreatic acinar cells. J Lab Clin Med 1998;132:294–302. 53 Couzigou P, Fleury B, Groppi A, Iron A, Coutelle C, Cassaigne A, et al: Role of alcohol dehydrogenase polymorphism in ethanol metabolism and alcohol-related diseases. Adv Exp Med Biol 1991;284:263–270. 54 Day CP, Bashir R, James OFW, et al: Investigation of the role of polymorphisms at the alcohol and aldehyde dehydrogenase loci in genetic predisposition to alcohol-related endorgan damage. Hepatology 1991;14:798– 801. 55 Dumas F, Coutelle C, Gerolami A, Groppi A, Cassaigne A, Couzigou P: Role of alcohol dehydrogenase polymorphisms in alcoholic patients with chronic pancreatitis. Gastroenterology 1993;104:A302.

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56 Haber P, Wilson J, Apte M, Korsten M, Pirola R: Individual susceptibility to alcoholic pancreatitis: still an enigma. J Lab Clin Med 1995; 125:305–312. 57 Chao YC, Young TH, Tang HS, Hsu CT: Alcoholism and alcoholic organ damage and genetic polymorphisms of alcohol metabolizing enzymes in Chinese patients. Hepatology 1997;25:112–117. 58 Kimura S, Okabayashi Y, Inushima K, Kochi T, Yutsudo Y, Kasuga M: Alcohol and aldehyde dehydrogenase polymorphisms in Japanese patients with alcohol-induced chronic pancreatitis. Dig Dis Sci 2000;45:2013–2017. 59 Frenzer A, Butler WJ, Norton ID, Wilson JS, Apte MV, Pirola RC, et al: Polymorphism in alcohol-metabolizing enzymes, glutathione Stransferases and apolipoprotein E and susceptibility to alcohol-induced cirrhosis and chronic pancreatitis. J Gastroenterol Hepatol 2002; 17:177–182. 60 Maruyama K, Takahashi H, Matsushita S, Nakano M, Harada H, Otsuki M, et al: Genotypes of alcohol-metabolizing enzymes in relation to alcoholic chronic pancreatitis in Japan. Alcohol Clin Exp Res 1999;23(suppl):85S–91S. 61 Yang B, O’Reilly DA, Demaine AG, Kingsnorth AN: Study of polymorphisms in the CYP2E1 gene in patients with alcoholic pancreatitis. Alcohol 2001;23:91–97. 62 Chao YC, Young TH, Chang WK, Tang HS, Hsu CT: An investigation of whether polymorphisms of cytochrome P4502E1 are genetic markers of susceptibility to alcoholic end-stage organ damage in a Chinese population. Hepatology 1995;22:1409–1414. 63 Hwang C, Sinskey AJ, Lodish HF: Oxidized redox state of glutathione in the endoplasmic reticulum. Science 1992;257:1496–1502. 64 Hayes JD, Pulford DJ: The glutathione Stransferase supergene family: regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance. Crit Rev Biochem Mol Biol 1995; 30: 445– 600. 65 Bartsch H, Malaveille C, Lowenfels AB, Maisonneuve P, Hautefeuille A, Boyle P: Genetic polymorphism of N-acetyltransferases, glutathione S-transferase M1 and NAD(P)H:quinone oxidoreductase in relation to malignant and benign pancreatic disease risk. The International Pancreatic Disease Study Group. Eur J Cancer Prev 1998;7:215–223. 66 Schneider A, Barmada MM, Whitcomb DC: Genetic analysis of the glutathion-S-transferase genes GSTT1 and GSTM1 in patients with sporadic, familial and hereditary pancreatitis (abstract). Pancreas 2002;25:449. 67 Rahman SH, Ibrahim K, Larvin M, Kingsnorth A, McMahon MJ: Association of antioxidant enzyme gene polymorphisms and glutathione status with severe acute pancreatitis. Gastroenterology 2004;126:1312–1322.

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68 Ockenga J, Vogel A, Teich N, Keim V, Manns MP, Strassburg CP: UDP glucuronosyltransferase (UGT1A7) gene polymorphisms increase the risk of chronic pancreatitis and pancreatic cancer. Gastroenterology 2003; 124: 1802–1808. 69 Verlaan M, te Morsche RH, Pap A, Laheij RJ, Jansen JB, Peters WH, et al: Functional polymorphisms of UDP-glucuronosyltransferases 1A1, 1A6 and 1A8 are not involved in chronic pancreatitis. Pharmacogenetics 2004; 14: 351– 357. 70 Fauchet R, Genetet B, Gosselin M, Gastard J: HLA antigens in chronic alcoholic pancreatitis. Tissue Antigens 1979;13:163–166. 71 Homma T, Kubo K, Sato T: HLA antigen and chronic pancreatitis in Japan. Digestion 1981; 21:267–272.

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72 Forbes A, Schwarz G, Mirakian R, Drummond V, Chan CK, Cotton PB, et al: HLA antigens in chronic pancreatitis. Tissue Antigens 1987; 30:176–183. 73 Wilson JS, Gossat D, Tait A, Rouse S, Juan XJ, Pirola RC: Evidence for an inherited predisposition to alcoholic pancreatitis. A controlled HLA typing study. Dig Dis Sci 1984; 29: 727– 730. 74 Maisonneuve P, Lowenfels AB, Mullhaupt B, Cavallini G, Lankisch PG, Andersen JR, et al: Cigarette smoking accelerates progression of alcoholic chronic pancreatitis. Gut 2005; 54: 510–514.

75 Uomo G, Rabitti PG: Chronic pancreatitis: relation to acute pancreatitis and pancreatic cancer. Ann Ital Chir 2000;71:17–21. 76 Talamini G, Bassi C, Falconi M, Sartori N, Pasetto M, Salvia R, et al: Early detection of pancreatic cancer following the diagnosis of chronic pancreatitis. Digestion 1999;60:554–561. 77 Talamini G, Bassi C, Falconi M, Frulloni L, Di Francesco V, Vaona B, et al: Cigarette smoking: an independent risk factor in alcoholic pancreatitis. Pancreas 1996;12:131–137. 78 Pae HO, Oh GS, Choi BM, Chae SC, Kim YM, Chung KR, et al: Carbon monoxide produced by heme oxygenase-1 suppresses T cell proliferation via inhibition of IL-2 production. J Immunol 2004;172:4744–4751. 79 Lee TS, Chau LY: Heme oxygenase-1 mediates the anti-inﬂammatory effect of interleukin-10 in mice. Nat Med 2002;8:240–246.

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Normal liver Steatosis (fatty liver) Hepatitis steatohepatitis (inflammation)

Fibrosis (excess collagen deposition) Cirrhosis (tissue scarring)

Fig. 1. Progression of alcoholic liver disease. Alcohol abuse primarily results in fatty liver (steatosis). Alcoholic steatohepatitis, or alcoholic hepatitis, is characterized by alcoholic steatosis accompanied by inﬂammation, leading to cirrhosis. Fibrosis may also result directly (without inﬂammation) from the pro-ﬁbrotic effects of alcohol.

hepatitis is characterized by hepatocyte injury and inﬂammation. Alcoholic ﬁbrosis or cirrhosis are characterized by excessive accumulation of extracellular matrix (ECM) proteins including collagen that occurs in most types of chronic liver diseases. Advanced liver ﬁbrosis results in cirrhosis, liver failure, and portal hypertension and often requires liver transplantation. In several different forms of liver injury it has been demonstrated that liver ﬁbrosis develops in response to inﬂammation of the liver. When alcoholic hepatitis is present, it may trigger ﬁbrosis and cirrhosis; however, ﬁbrosis and cirrhosis sometimes develop without a preceding stage of alcoholic hepatitis [4, 5] (ﬁg. 1). Diagnosing the stage of ALD is important for the management and treatment of ALD. Together with physical examination and laboratory tests of liver disease, the ﬁrst necessary step in diagnosing ALD is to determine whether the patient is abusing alcohol. However, this is not always easy. Laboratory tests are usually used in the diagnosis of ALD. The level of the enzyme aspartate aminotransferase (AST) is greater than that of alanine aminotransferase (ALT). When the ratio of AST to ALT is greater than 2, the most likely diagnosis is ALD. Other laboratory tests including -glutamyltransferase, mean corpuscular erythrocyte volume and carbohydrate-deﬁcient transferrin are frequently used to diagnose ALD. Although the diagnosis of ALD made by clinical features (reported alcohol intake and signs of chronic liv-

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er disease) and laboratory features are fairly sensitive (79%) and speciﬁc (98%) for the histological diagnosis of ALD [6], other diagnostic tests like ultrasonography and histology by liver biopsy are sometimes helpful for diagnosis.

Clinical Syndromes of ALD

Alcoholic Steatosis Fatty liver, or alcoholic steatosis, is the earliest event in the pathogenesis of ALD. Up to 90% of alcoholics feature hepatic steatosis [2]. Alcoholic steatosis develops already in individuals who experience a short time (a few days) of binge drinking (180 g/day). Alcoholic steatosis is usually asymptomatic with no clinical symptoms except for an enlarged liver (hepatomegaly). Histological ﬁndings of fatty liver are characterized by the excessive accumulation of lipids in large (macrovesicular) and small (microvesicular) droplets inside the hepatocytes. Fatty liver can be reversed if alcohol consumption is stopped or signiﬁcantly reduced [7], but the condition can lead to inﬂammation (steatohepatitis or alcoholic hepatitis) and ﬁnally to cirrhosis, if alcohol consumption is not reduced or stopped. Studies in the 1960s to 1980s have shown that 5–15% of patients who are initially diagnosed with alcoholic fatty liver developed cirrhosis [5, 8]. Teli et al. [9] reported that patients with a histological diagnosis of histologically proven ‘pure’ alcoholic fatty liver with no evidence of ﬁbrosis or alcoholic hepatitis had a 10% risk of developing cirrhosis and 18% risk of cirrhosis or ﬁbrosis over a following period of 10.5 years. Some patients with steatosis develop ﬁbrosis around terminal hepatic venules (perivenular ﬁbrosis) or liver parenchymal cells (pericellular ﬁbrosis; ﬁg. 2). Perivenular ﬁbrosis at the fatty liver stage is likely to progress to cirrhosis if the patients continue to consume alcohol [5]. The prevalence of obesity was 19.8% in 2000 and continues to increase among US adults [10]. Although obesity is a known risk factor for non-alcoholic fatty liver disease [11], several reports have shown that obesity also potentiates the severity of alcohol-induced liver disease: obesity increased the risk for steatosis in heavy drinkers [12]; the body mass index is an independent risk factor for ﬁbrosis in alcohol-induced liver disease [13], and the presence of excess weight for at least 10 years is a risk factor for steatosis, acute alcoholic hepatitis, and cirrhosis in alcoholics [14]. A recent report also indicated that pa-

Adachi/Brenner

Fig. 2. Pericellular ﬁbrosis in alcoholic steatohepatitis. Also noted

is mild microvesicular and macrovesicular steatosis. Masson trichrome. !200.

tients with alcoholic fatty liver disease had a higher risk of developing cirrhosis and mortality than those with non-alcoholic fatty liver disease [15]. Steatohepatitis and Alcoholic Hepatitis Alcoholic steatohepatitis or alcoholic hepatitis is characterized by alcoholic steatosis accompanied by acute or chronic inﬂammation and a variable amount of ﬁbrosis. Histological features of alcoholic hepatitis include neutrophilic inﬁltration, various degrees of ﬁbrosis, hepatocyte necrosis and Mallory bodies (ﬁg. 3). About 10–35% of all alcoholics have changes in liver histology consistent with alcoholic hepatitis [2]. The risk of developing cirrhosis is increased in patients with alcoholic hepatitis. Approximately 40% of those with alcoholic hepatitis were found to have cirrhosis after repeated biopsy 5 years later [16]. The probability of developing cirrhosis in patients with alcoholic hepatitis is approximately 10–20%/year, and approximately 70% of the patients with alcoholic hepatitis will ultimately develop cirrhosis [17, 18]. In addition, severe alcoholic hepatitis is a rare clinical syndrome that presents with fever, jaundice, bleeding diathesis and hepatic encephalopathy and has a poor prognosis. The short-term mortality rate of severe alcoholic hepatitis is approximately 50% [19]. A special syndrome of severe alcoholic hepatitis is called Zieve’s syndrome. It features a triad of jaundice, hyperlipidemia (especially high triglycerides), and hemolytic anemia.

Clinical Syndromes of Alcoholic Liver Disease

Fig. 3. Histological features of alcoholic hepatitis with neutrophil inﬁltration. Inﬁltration of neutrophils, hepatocyte necrosis and Mallory bodies. HE. !400.

Fibrosis and Alcoholic Cirrhosis Fibrosis is considered a model of the wound-healing response to chronic liver injury. The risk of developing cirrhosis is increased in patients with alcoholic hepatitis; however, ﬁbrosis can occur in the absence of alcoholic hepatitis [4, 5]. In these patients, perivenular ﬁbrosis at the fatty liver stage is a useful pre-cirrhotic marker. Patients with alcoholic cirrhosis have clinical features similar to those with cirrhosis of other etiology. However, alcohol consumption continues to worsen the prognosis even after cirrhosis has developed. Patients with clinically compensated cirrhosis who become abstinent have a 90% chance of surviving for 5 years. In contrast, if these same patients continue to drink, their chance of survival falls to about 70%. Once signs of clinical decompensation develop in patients with alcohol-induced cirrhosis, patients who stop drinking can expect a 5-year survival of about 60% versus only 30% if they continue to drink alcohol [20–22]. Decompensated alcoholic cirrhosis is associated with short survival, and liver transplantation is often indicated as the only effective therapy [23, 24]. Survival rates after liver transplantation are similar among alcoholics and non-alcoholics [25, 26]. In addition to a medical assessment, a psychosocial assessment of cirrhotic patients should be carefully judged to establish long-term abstinence after liver transplantation [24, 27, 28].

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Pathogenesis of Clinical Syndromes of ALD

Pathogenesis of Alcoholic Steatosis Impaired Fatty Acid Oxidation One of the early targets of ethanol toxicity is mitochondrial fatty acid oxidation. Impaired fatty acid oxidation plays a key role in alcoholic steatosis. Alcohol has been shown to decrease hepatic fatty acid oxidation in vivo and in vitro. Alcohol metabolism alters the NADH/NAD+ redox potential in the liver, which in turn impairs -oxidation and tricarboxylic acid cycle activity [29, 30]. In addition, both long- and short-term alcohol consumption has been shown to suppress the activity of carnitine palmitoyl transferase-I, a rate-limiting enzyme involved in the transport of long-chain fatty acids into mitochondrial matrix. Increase in Fatty Acid Synthesis In addition to the suppression of fatty acid oxidation, enhanced fatty acid synthesis also contributes to alcoholic steatosis. Chronic ethanol consumption can increase fatty acid synthesis in humans and rodents by inducing the expression of key enzymes in the lipogenic pathway. These lipogenic enzymes are now known to be regulated by the transcription factor sterol regulatory element binding proteins (SREBPs). In the liver, SREBP-1c is involved in fatty acid synthesis and SREBP-2 is involved in the regulation of cholesterol synthesis. A substantial increase in the amount of mature SREBP-1 protein was found in the livers of ethanol-fed mice [31]. Moreover, ethanol feeding increased the mRNA expression of several known hepatic lipogenic SREBP-1 target genes including fatty acid synthase, steroyl-CoA desaturase, malic enzyme, ATP citrate lyase, and acetyl-coenzyme A carboxylase, indicating that ethanol-mediated induction of SREBP-1 maturation may be associated with the increase in expression of these genes [32]. The levels of the enzymes involved in fatty acid oxidation and synthesis are also predominantly controlled by peroxisome proliferator-activated receptor- (PPAR). PPAR controls transcription of a set of genes containing peroxisome proliferator response elements when dimerized with retinoid X receptors, which are involved in free fatty acid transport and oxidation. PPAR knockout animals develop fatty liver and obesity [33]. Ethanol feeding of mice resulted in the reduction of retinoid X receptor levels and treatment with the PPAR ligand cloﬁbrate during ethanol feeding resulted in an increase in the level of PPAR protein and mRNA levels of PPAR target

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genes, and attenuation of fat accumulation in the liver [34]. Taken together, these studies suggest that ethanol or its metabolites may increase hepatic lipogenesis through SREBP-1 and PPAR. Pathogenesis of Alcoholic Hepatitis Many patients with steatosis never progress to inﬂammation (steatohepatitis) or ﬁbrosis [9]. This suggests that the occurrence of inﬂammation, in addition to steatosis, requires the presence of some other factors (a ‘second hit’) [35]. Relevant factors include metabolism of alcohol to toxic products, oxidant stress, acetaldehyde and its adducts, the action of endotoxin on Kupffer cells. However, the pathogenesis of alcoholic hepatitis is multifactorial. Endotoxin, Kupffer Cell Activation and Cytokine-Induced Liver Injury Gut-derived endotoxin, including toxic lipopolysaccharide (LPS), is another important element in the pathogenesis of alcohol-induced liver damage [36]. Endotoxin may trigger both cytokine release and oxidative stress. For example, studies have found that patients with ALD have elevated levels of endotoxin circulating in the blood [37]. In the liver, endotoxin activates Kupffer cells, which play a major role in liver inﬂammation by releasing reactive oxygen species (ROS) and cytokines [38]. Endotoxin binds to a LPS-binding protein and this complex binds CD14, a receptor on the surface of Kupffer cells. CD14 interacts with the membrane spanning Toll-like receptor type 4 (TLR4; ﬁg. 4). In experiments with rodents, eliminating endotoxin from the intestine using oral antibiotics [39] or lactobacillus [40] attenuated alcohol-induced liver injury. Furthermore, blocking signals of LPS in Kupffer cells using either LPS-binding protein knockout mice [41], CD14 knockout mice [42] or TLR4 mutant mice [43] attenuated alcoholic liver injury. These reports strongly suggest the possible role of endotoxin in the development of ALD (for summary see table 1). Proinﬂammatory cytokines produced by activated Kupffer cells are suggested to be involved in ALD. Clinical studies have demonstrated that patients with ALD have increased levels of the proinﬂammatory cytokines IL-1, IL-6, and TNF- as well as the chemokine IL-8 and other cytokines [44, 45]. Among these proinﬂammatory cytokines, TNF- was postulated to be a key mediator cytokine of ALD. In animal models of alcoholic liver injury, alcoholic liver injury is signiﬁcantly attenuated by administration of antibodies against TNF- [46] and is

Adachi/Brenner

Kupffer Cell NADPH oxidase

O2 O2

ONOO –

MD-2

iNOS

TLR4 NFκB LBP LPS

NO [ONOO –] *

ROS

EtOH

TNFα

CD14

a-OH-Ethyl radical

Y Fig. 4. Model of endotoxin release, Kupffer

Endotoxin

cell activation and liver injury in alcoholic liver disease. Following chronic alcohol ingestion, endotoxin released from gramnegative intestinal bacteria moves from the gut into the bloodstream and into the liver. There, endotoxin activates Kupffer cells, resulting in the production of signiﬁcant amounts of cytotoxic factors including cytokines, superoxide radicals and nitric oxide.

Table 1. Protection against alcoholinduced liver injury in enteral diet: relationship to bacterial translocation and Kupffer cell activation

TNF-R1 ROS

Ethanol

Liver injury

Gut

Hepatocyte

Target

Blocked ALT?

Blocked steatosis?

Blocked inﬂammation and necrosis?

Blocked Blocked ROS NFB signal(s)? and/or TNF-?

Nonabsorbable ABX LBP KO CD14 KO TLR4 mutant TNFR1 KO P47phox KO iNOS KO

+++ ++ +++ ++ +++ +++ ++

+++ ++ ++ ++ +++ +++ ++

+++ ++ +++ ++ +++ +++ ++

+++ NS NS NS – +++ NS

+++ +++ +++ +++ – +++ ++

The roles of bacteria-derived endotoxin and Kupffer cells were elucidated by rodent models of alcoholic liver injury, suggesting a critical role of Kupffer cells in alcoholic liver disease.

diminished in TNF- receptor-1 knockout mice [47], suggesting that TNF- plays an important role in the development of alcohol-induced liver injury. Furthermore, treatment with thalidomide, a compound that inhibits TNF- production in Kupffer cells, completely prevents alcoholic liver injury in rats [48].

TNF- is also implicated to play a key role in the pathogenesis of liver injury associated with severe alcoholic hepatitis. The plasma levels of TNF- are increased in patients with severe alcoholic hepatitis and may correlate with mortality [49, 50]. Based on results from animal and clinical studies, recent reports suggested that ei-

Clinical Syndromes of Alcoholic Liver Disease

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259

ther the TNF- inhibitor pentoxifylline [51] or an antiTNF- monoclonal antibody [52] may be of beneﬁt in patients with severe alcoholic hepatitis. The detrimental results of treatment with the combination of prednisolone and a high-dose anti-TNF- antibody probably reﬂect a certain exaggerated immunosuppression with increased infections by this regimen [53]. Oxidative Stress Alcohol induces oxidative stress in the liver by either enhancing the production of ROS and/or decreasing the level of endogenous antioxidants, leading to tissue damage. Many studies have indicated that oxidative stress plays a role in the initiation and progression of ALD [54]. The sources of ROS include the mitochondria and cytochrome P450 2E1 (CYP2E1) in hepatocytes, and NAD(P)H oxidase in inﬂammatory cells. In hepatocytes, mitochondria are a signiﬁcant source of ROS during ethanol metabolism [55]. Induction of CYP2E1 by ethanol is also a central pathway by which ethanol generates oxidative stress in hepatocytes [56]. Moreover, antioxidant mechanisms are also impaired after alcohol consumption and therefore contribute to liver injury [54, 57]. In addition to producing cytokines, activated Kupffer cells are the major source of ROS in the liver. One important ROS is superoxide which is generated by the enzyme NADPH oxidase in Kupffer cells. Superoxide production was prevented by inhibiting p47phox, a critical subunit of NADPH oxidase in activated phagocytes, resulting in the reduction of alcohol-induced liver injury [58]. Superoxide reacts with nitric oxide (NO) to form peroxynitrite, another form of a toxic molecule. NO is also produced by Kupffer cells via induction of inducible NO synthase (iNOS). Recent studies have shown that iNOS knockout mice are protected completely against oxidative stress caused by ethanol [59]. These reactive mediators also induce lipid peroxidation [60]. Lipid peroxidative products such as malondialdehyde and 4-hydroxynonenal are increased in ALD [61] and may contribute to liver injury and ﬁbrosis [60]. Acetaldehyde Acetaldehyde is the most important metabolite of ethanol leading to liver damage. The toxicity of acetaldehyde is due, at least in part, to its capacity to form adducts with intracellular proteins. The occurrence of acetaldehydederived protein adducts are present in ALD, which coincide with the degree of alcoholic liver injury [60, 62, 63]. In addition, acetaldehyde-protein adducts can trigger an abnormal immune response characterized by the produc-

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tion of antibodies directed against acetaldehyde epitopes. Antibodies to these adducts can be found in the sera of heavy drinkers and in mice fed ethanol [64–66]. Adiponectin Adiponectin is a hormone exclusively secreted from adipose tissue that acts as an anti-diabetic and anti-atherogenic adipokine and has recently been shown to be a promising candidate for the treatment of obesity-associated metabolic syndromes [67, 68]. Adiponectin and TNF- suppress each other’s production and also antagonize each other’s action in their target tissues [69]. A recent report showed the potential role of adiponectin in the treatment of ALD [70]. A chronic ethanol diet decreased circulating concentrations of adiponectin and reduced adiponectin expression. Whereas chronic ethanol feeding signiﬁcantly decreased the rate of hepatic fatty acid oxidation and reduced the activities of carnitine palmitoyl transferase-I, acetyl-coenzyme A carboxylase, and fatty acid synthase; adiponectin treatment restored all these activities. Adiponectin also attenuated alcohol-induced steatosis and liver injury, suggesting the pivotal role of adiponectin in the pathogenesis of alcoholic steatosis and steatohepatitis. Pathogenesis of Fibrosis and Cirrhosis Fibrosis is recognized as a wound-healing response to a variety of chronic stimuli and is characterized by an excessive deposition of ECM proteins of which type-I collagen predominates. This excess deposition of ECM proteins disrupts the normal architecture of the liver resulting in pathophysiological damage to the organ, leading to organ failure and death. Hepatic stellate cells (HSCs) change from a quiescent to an activated phenotype during ﬁbrogenesis and are the major source of ECM proteins in hepatic ﬁbrosis, including type-I collagen. During activation HSCs undergo transition into proliferative, ﬁbrogenic, proinﬂammatory, and contractile myoﬁbroblasts [71, 72] (ﬁg. 5). A number of factors have been proposed to initiate and perpetuate the ﬁbrogenic process in stellate cells, including enhanced oxidative stress and lipid peroxidation, production of cytokines, growth factors, and acetaldehyde. Inﬂammation and necrosis in the liver (hepatitis) trigger ﬁbrosis as a part of the wound-healing and scarring response. Therefore, it makes sense to postulate that alcoholic hepatitis is the main mechanism for the development of alcoholic ﬁbrosis and cirrhosis. Transforming growth factor (TGF)- is a key proﬁbrotic cytokine and is mitogenic in human HSCs [73]. The TGF-1-activated

Adachi/Brenner

Initiation phase Quiescent HCS

Perpetuation phase Smooth muscle a-actin

Retinoid droplets

Activated HSC

Autocrin cytokin s

Proliferation

Cytokine receptors Proliferative cytokines (PDGF)

Fibrogenic stimulus - Signals from Kupffer cells or hepatocytes 1) Cytokines 2) Oxidative stress and lipid peroxidation products 3) Acetaldehyde adducts

Fibrogenic cytokines (TGFb) Type IV collagenase

Fibrogenesis Matrix induced activati

Fig. 5. Cellular mechanisms of liver ﬁbrosis. Alcohol abuse induces mediators that induce stellate cell activation. Activated Kupffer cells and damaged hepatocytes release inﬂammatory cytokines and other soluble factors. This inﬂammatory milieu stimulates the activation of resident hepatic stellate cells (HSCs) into ﬁbrogenic myoﬁbroblasts. Activated HSCs also secrete cytokines that perpetuate their activated state.

Smad-signaling pathway stimulates experimental hepatic ﬁbrosis and is a potential target for therapy [74]. ROS induce HSC activation, proliferation and collagen gene expression in vitro [75, 76]. Lipid peroxidation products, derived from injured hepatocytes, endothelial and Kupffer cells, may be important signaling molecules in stellate cell activation [77]. Moreover, depletion of antioxidants in stellate cells also occurs and could be related to their ﬁbrogenic capacity [78]. ROS produced by inﬂammatory cells, either lymphocytes or polymorphonuclear cells, activate HSCs via lipid peroxidation, and lead to increased secretion of collagen [79]. Acetaldehyde stimulates the production of several ECM including type-I collagen and enhance the expression of TGF-1 in HSCs [80, 81] and ﬁbroblasts [82]. In histological examinations of liver biopsies from alcoholics, protein-acetaldehyde adducts were co-localized within the ECM in the liver and the presence of extracellular

Clinical Syndromes of Alcoholic Liver Disease

acetaldehyde adducts was signiﬁcantly correlated to progression of liver ﬁbrosis, suggesting a pivotal role for acetaldehyde in alcoholic ﬁbrosis and cirrhosis [63].

Conclusion

ALD continues to be major health problem with respect to both morbidity and mortality. Clinical studies combined with rodent models have established a spectrum of ALD, from steatosis to steatohepatitis, ﬁbrosis, and cirrhosis. New insights into the pathogenesis of ALD include the key roles of bacterial translocation, the excess production of TNF-, TGF-, and ROS, and other factors such as the shortage of adiponectin production. These new insights will lead to new speciﬁc therapies for the treatment of alcoholic hepatitis and alcoholic liver ﬁbrosis.

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263

Normal liver

Fibrotic liver Hepatocyte regeneration

Macrovesicular steatosis

Hepatocyte apoptosis/ necrosis

Chronic ETHANOL Low density ECM

Interstitial ECM/ fibrillar collagen

Quiescent HSC

Basal membrane

Quiescent Kupffer cell

Fenestrated endothelium

Defenestrated endothelium

Microvilli loss

Sinusoid Activated HSCs

Sinusoid

Activated Kupffer cell/ macrophage

Fig. 1. Schematic representation of alterations in the liver during ethanol-induced ﬁbrogenesis. Chronic alcoholic injury of the liver causes accumulation of macrovesicular fat in hepatocytes. Quiescent, vitamin A-storing hepatic stellate cells (HSCs) become activated, e.g. triggered by paracrine stimulation from activated Kupffer cells/ macrophages. They transdifferentiate into myoﬁbroblast-like cells, producing excessive amounts of extracellular matrix (ECM), mainly ﬁbrillar collagen in the space of Dissé. This leads to defenestration of the sinusoidal epithelium and formation of basal membranes. Furthermore, reactive oxygen species-triggered hepatocyte cell death contributes to HSC activation. HSCs proliferate and migrate towards the site of hepatocellular injury. Finally, ethanol-induced liver cirrhosis features mostly micronodular regeneration of hepatocytes as part of an irregular remodeling of the liver.

in pericentral and perisinusoidal areas, whereas ﬁbrosis induced by chronic viral hepatitis predominantly occurs around portal tracts [8, 9].

Hepatic Stellate Cell Activation in ALD

Hepatic stellate cells (HSCs; also known as Ito cells, fatstoring cells or hepatic lipocytes) are mainly responsible for increased synthesis and deposition of ECM in the liver during ﬁbrogenesis [7–11]. HSCs are perisinusoidal cells that reside in healthy liver in a quiescent state. Their main function is storage and homeostasis of vitamin A and other retinoids, which are retained in cytoplasmatic lipid droplets as retinyl esters together with triacylglycerides. Further functions comprise ECM homeostasis, including production and degradation of normal hepatic ECM, production of apolipoproteins, prostaglandins and cytokines as well as regulation of sinusoidal blood ﬂow [12, 13]. Following a ﬁbrogenic stimulus, HSCs undergo a complex activation process in which the cells change from a quiescent to an activated myoﬁbroblast-like phenotype, and proliferate, migrate to the site of liver injury and produce excessive amounts of ECM resulting in scarring of

Molecular Mechanisms of Alcohol-Induced Hepatic Fibrosis

the liver. Alcohol-induced activation of HSCs occurs as a response to chronic alcohol uptake with considerable loss of functional hepatocellular tissue, whereas a single acute binge of ethanol does not cause HSC activation [10]. Activation of HSCs (ﬁg. 2) can be subdivided into two phases, that is (i) initiation and (ii) perpetuation [10, 11, 13, 14]. Initiation results from paracrine stimulation by impaired neighboring cells, e.g., injured hepatocytes, endothelial cells and activated Kupffer cells, as well as from early and subtle changes in ECM composition. Some authors divide the initiation phase into a pre-inﬂammatory phase before and an inﬂammatory phase after involvement of immune cells [2, 15]. Initiation is associated with transcriptional changes in HSCs involving rapid induction of immediate early genes encoding, e.g., for cytokines or membrane receptors, rendering the cells responsive to cytokines and other local stimuli, such as acetaldehyde. As a consequence, a phenotypical transdifferentiation is evident. The mechanisms of HSC activation originate already in the early stages of ALD, steatosis and steatohepatitis (ﬁg. 1). One mechanism by which hepatic steatosis causes HSC activation is generation of ROS produced in meta-

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Proliferation

CHRONIC ALCOHOLIC LIVER INJURY

Contractility

(ROS, actetaldehyde, aldehyde-protein adducts, lipid peroxides, apoptotic/necrotic hepatocytes, etc.)

Fibrogenesis PDGF ET-1

TGF-β 1 Integrins

Activation

Apoptosis

(Regression?) MMPs

ROS, various cytokines Endotoxin

Activation

Chemotaxis (M-CSF, MCP-1)

Autocrine selfstimulation of quiescent HSCs

Matrix degradation

Inflammatory cells (Kupffer cells, neutrophils, T-cells)

Fig. 2. Schematic overview of the different aspects of hepatic stellate cell (HSC) activation and the main cyto-

kines/mediators involved. After activation, the major phenotypic changes include ﬁbrogenesis, proliferation, contractility, matrix degradation and chemotaxis. Activated HSCs may also undergo apoptosis, representing a major ﬁeld of research for anti-ﬁbrotic therapy. A special aspect represents inﬂammatory cells in alcoholic liver disease (ALD). Reactive oxygen species (ROS) and various cytokines derived from endotoxin-activated inﬂammatory cells are main contributors to HSC activation in ALD. ET-1 = Endothelin-1; MCP-1 = monocyte chemotactic protein; M-CSF = macrophage-colony stimulating factor; MMPs = metallo-matrix proteinases; TGF-1 = transforming growth factor-1.

bolically impaired hepatocytes. Reactive oxygen species (ROS) can cause HSC activation alone or in combination with other factors that may activate HSCs in ALD, such as cytokines or lipid oxidation products [16–20]. Persisting alcohol consumption causes a gradual involvement of inﬂammatory cells. Chronic inﬂammatory conditions with an abundance of proinﬂammatory cytokines, including TNF-, IL-1 or IL-6, induce and perpetuate the activation of HSCs [21, 22]. Activated HSCs, in turn, may amplify inﬂammation through release of neutrophil and monocyte chemoattractants and upregulation of adhesion molecules that are required for leukocyte adhesion and transmigration [21–23].

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Furthermore, the increased serum levels of gut-derived endotoxin most likely contribute directly to the perpetuation of HSC activation in ALD. It has been shown that activated HSCs express the components of endotoxin-recognizing receptors, including CD14, TLR4, and MD2. Endotoxin induces activation of the proinﬂammatory NFB and JNK pathways, followed by expression of chemokines and adhesion molecules in activated human HSCs [24]. ROS, either from hepatocytes or activated Kupffer cells, have an articulate paracrine effect on quiescent HSCs [16, 17] (ﬁg. 2). Their activity is further augmented in vivo by depletion of cellular antioxidants like glutathi-

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one, a typical feature of ALD [25]. The proﬁbrogenic effect of ROS was conﬁrmed by the ﬁnding that ROS-scavenging enzymes, such as the superoxide dismutase system (SOD1, SOD2 and SOD3), prevent ALD in animal models [26, 27]. In vitro experiments emphasize the importance of ROS in the mechanism of HSC activation: medium derived from freshly isolated hepatocytes exposed to oxidative stress increases proliferation and collagen synthesis in cultured HSCs [28]. Moreover, augmented ethanol-induced ROS production in CYP2E1-overexpressing HSCs leads to enhanced collagen 1(I) gene expression [29]. By changing the cellular redox state, ROS also modulate the activity of transcription factors involved in HSC activation and ﬁbrogenesis, such as c-Jun/ AP-1, NFB, SP1 or c-Myb [30]. Ethanol metabolism modiﬁes the cellular redox state in the liver by altering the ratio of NAD/NADH and NADP/NADPH, which leads to increased production and accumulation of lactic acid, another metabolite known to induce HSC activation and ﬁbrogenesis [31]. Beside CYP2E1 [29, 31–34], NADPH oxidase plays an additional key role in oxidant radical formation and activation of HSC. NADPH oxidase, mainly expressed in activated Kupffer cells [16, 17], may activate HSCs by generating H2O2, which functions directly as a second messenger for collagen 1(I) gene upregulation [35, 36]. Recent studies underline the importance of NADPH oxidase-derived ROS in hepatic ﬁbrogenesis mediated by angiotensin II, a powerful proﬁbrogenic cytokine and mitogen [37, 38]. Thus, activated HSCs themselves are a signiﬁcant source of ROS [38, 39]. Hepatic hypoxia induced by ethanol metabolism holds another key function in ethanol-related activation of HSCs. Ethanol-induced hypoxia and hepatocellular damage are augmented in pericentral areas of the liver acinus. Hypoxia causes upregulation of the transcription factor hypoxia-inducible factor-1, which upregulates the transcription of the cytokine vascular endothelial growth factor (VEGF), another strong paracrine and autocrine inducer of HSC activation [40, 41]. Ethanol itself, and even more its ﬁrst metabolization product, acetaldehyde, may have activating effects on HSCs [31] (ﬁg. 2). Acetaldehyde can directly upregulate collagen genes [30, 31, 42]. However, acetaldehyde-derived lipid peroxides, such as 4-hydroxy-nonenal or malondialdehyde, seem rather to promote hepatic ﬁbrogenesis in already activated HSCs than to initiate HSC activation [19, 43–46]. Further, fatty acid ethyl esters (ethanol metabolites generated in a non-oxidative fashion and esteriﬁed with fatty acids) activate quiescent HSCs via a

mitogen-activated protein kinase (MAPK)-dependent pathway [47]. Finally, sinusoidal endothelial cells also participate in ethanol-related HSC activation. Injury of sinusoidal epithelial cells by ROS or acetaldehyde stimulates production of certain ﬁbronectin isoforms in these cells which then activate HSCs. Moreover, damaged epithelial cells convert latent transforming growth factor (TGF)-, the most ﬁbrogenic cytokine to date, into its active form through plasmin activation [11].

Molecular Mechanisms of Alcohol-Induced Hepatic Fibrosis

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Mechanisms of Excessive Accumulation and Irregular Deposition of ECM in Ethanol-Induced Liver Fibrosis

Upregulation of collagen synthesis is one of the most striking molecular responses of activated HSCs and is mediated by both transcriptional and post-transcriptional mechanisms. The type I collagen molecule is a heterotrimer composed of two 1(I) chains and one 2(I) chain [48]. The mechanism of collagen 1(I) and 2(I) accumulation during liver ﬁbrogenesis is similar regardless of the etiology of chronic liver injury. However, ethanol-induced liver ﬁbrosis exhibits some special characteristics: acetaldehyde induces the upregulation of collagen 1(I) and 2(I) in HSCs [49–51]. In particular, acetaldehyde activates transcription of both collagen 1(I) and 2(I) genes via the collagen transcription factor p35/EBP [52, 53]. In activated HSCs, the steady-state level of collagen 1(I) mRNA increases 60- to 70-fold compared to quiescent HSCs. While the transcription rate increases about 3-fold, the half-life of collagen 1(I) mRNA increases 16fold from 1.5 h in quiescent HSCs to 24 h in activated HSCs [54]. This indicates a major role for post-transcriptional regulation. Increased stability of collagen 1(I) mRNA is mediated by sequences in the 3 untranslated region (UTR) of the transcript, which interacts with a conserved stem-loop structure at the 5 end of the collagen 1(I) mRNA [55]. The RNA-binding protein CP binds to the 1(I) collagen 3-UTR, stabilizes this RNA and blocks RNA degradation in activated but not in quiescent HSCs [56]. Moreover, the interaction of the protein TRAM2 with the Ca2+ pump of the endoplasmatic reticulum, SERCA2b, is essential for triple helical collagen folding [57]. The 5-stem loop of the collagen 1(I) mRNA is further required to form triple helical collagen ﬁbrils [57, 58]. After post-translational modiﬁcations, type I collagen molecules are packed into ﬁbrils in the ECM. The formation of covalent intermolecular cross-links of

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collagen is the ﬁnal modiﬁcation step of collagen ﬁbrils. This process provides the ﬁbrils with mechanical strength. In cirrhotic livers, the mature non-reducible collagen cross-links are signiﬁcantly higher than in normal liver. Therefore, turnover and degradation of collagen is impaired in cirrhotic livers resulting in net collagen accumulation [48]. The proteolytic mechanisms of matrix degradation, which are a key feature of the ECM homeostasis in normal liver, are repressed and impaired during liver ﬁbrogenesis. An altered matrix metalloproteinase activity leads to remodeling of hepatic ECM and accelerates ﬁbrogenesis by increased net ECM production and HSC activation. HSCs are in particular a key source of matrix metalloproteinase-2 (MMP-2) and stromelysin/MMP-3, which degrade normal subendothelial ECM [59–64], thereby promoting replacement by and accumulation of ﬁbril-forming collagen, which further increases HSC proliferation and MMP-2 production in a positive feedback loop [63, 65]. Through upregulation of inhibitory proteins, the tissue inhibitor of metalloproteinase-1 and -2 (TIMP-1 and -2), activated HSCs inhibit the activity of interstitial collagenases, thus additionally favoring accumulation of scar tissue [60–62]. The most important stimulus for ECM production by HSCs in all chronic liver diseases including alcohol-induced liver ﬁbrosis is TGF-. TGF- production is markedly increased in experimental and human hepatic ﬁbrosis [11]. The cytokine is initially secreted by damaged hepatocytes, activated Kupffer cells or platelets. Especially its isoform TGF-1 is probably the most powerful and widely distributed pro-ﬁbrogenic mediator in the body. Deposition of ECM is part of a TGF--dependent physiological wound-healing response to tissue injury that may progress to pathological ﬁbrosis when the damaging agent is chronically provided [66]. TGF- induces expression of ﬁbrillar and nonﬁbrillar collagens, other interstitial matrix components including ﬁbronectin and tenascin, the basement membrane components laminin and entactin, and membrane proteoglycans including perlecan and biglycan [67]. Thus, TGF- contributes to ECM accumulation and irregular deposition in ﬁbrotic tissue, e.g. by forming basal membranes that cause defenestration of hepatic sinusoids. Moreover, TGF- signaling decreases expression of various MMPs, which leads to hampered degradation and acceleration of ECM accumulation [68]. Transcriptional upregulation of the TGF- gene and of its cell membrane receptors is one feature of cultureactivated HSCs [69]. In addition, TGF- activity is enhanced in activated HSCs through proteolytic transfor-

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mation of latent TGF- into the active cytokine by a urokinase-type plasminogen activator [70, 71]. Release and activity of TGF- are controlled by a number of intracellular and ECM-deposited interacting proteins. For example, plasmin treatment of cultured HSCs induces release of TGF- from the matrix accompanied by an increased TGF--dependent gene response, e.g., upregulation of Smad7 mRNA expression [72], indicating that plasmin participates in the activation process of latent TGF-. Furthermore, platelet-derived growth factor-BB-induced thrombospondin-1 expression enhances TGF- effects in HSCs [73]. TGF- signaling occurs after binding to its type I and II receptors [74–76]. In HSCs it became evident that TGF- signaling is modulated during transdifferentiation from quiescent to activated HSCs. In quiescent HSCs, TGF- leads to phosphorylation of the transcription factor-like intracellular proteins Smad2 and Smad3 through a serine/threonine kinase-mediated process. Smad2 and 3 form oligomeric complexes with Smad4, which then translocate into the nucleus. This complex activates the TGF- reporter construct (CAGA)9-MLPluciferase, and leads to transcription of target genes, such as 1 and 2(I) collagen, or Smad7 [77–79]. Smad7 acts as an inhibitor of this mechanism [80, 81]. Moreover, this TGF- pathway decreases the DNA synthesis in quiescent or early activated HSCs [77]. These ‘acute’ effects of TGF- do not occur in fully activated HSCs, in which TGF-/TRII/Alk5 complex formation and TGF--dependent Smad2/3 activation and Smad7 induction are signiﬁcantly reduced. Interestingly, Smad3 is increased [78] and constitutively phosphorylated by p38 MAPK, a mechanism that contributes to ECM production in activated HSCs, both in vitro and in vivo [82]. A major role for Smad3 in ﬁbrogenesis was also shown in carbon tetrachloride (CCl4)-treated Smad3-deﬁcient mice, providing that maximal expression of collagen type I and inhibition of proliferation, but not HSC activation requires Smad3 in HSCs, as assessed by the expression of the speciﬁc activation marker -smooth muscle actin (-SMA) [83]. Further studies indicate that Smad2 and Smad3 signal via independent pathways in HSCs and that Smad3 plays an important role in the morphological and functional maturation of hepatic myoﬁbroblasts [84]. In alcoholic liver ﬁbrosis, acetaldehyde elevates steadystate levels of TGF- mRNA [50], promotes activation of latent TGF- protein and upregulates the expression of its receptor type II (TRII) [85]. Reducing TGF- protein levels causes a decrease in acetaldehyde-induced collagen 2(I) gene transcription in activated HSC [42, 86],

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whereas early acetaldehyde-dependent upregulation of collagen is independent of TGF- and modulated by PI3kinase [51].

Novel Molecular Anti-Fibrotic Treatment Strategies

While avoiding the damaging agent, e.g. alcohol, still remains the most important healing approach, efforts have been undertaken to blunt the process of ﬁbrogenesis at the molecular level or to speciﬁcally induce cell death in activated HSCs. Many of the novel molecular therapeutic approaches target the most prominent proﬁbrogenic signaling pathway, initiated by TGF-. For example, adenoviral overexpression of dominant negative TRII attenuated dimethylnitrosamine (DMN)-induced liver ﬁbrosis in rats [87]. Moreover, an adenovirus expressing an entire ectodomain of human TRII fused to the Fc portion of human IgG was similarly efﬁcient in the DMN model without apparent systemic or local side effects [88]. This result indicates that the transient systemic presence of soluble TRII is sufﬁcient to inhibit TGF1 action and might therefore be a useful approach for the treatment of different diseases that involve TGF- signaling without the necessity to directly target the affected organ. Another strategy of TGF- neutralization is targeting the activation process of latent TGF-. Thus, the serine protease inhibitor camostat mesilate attenuated hepatic ﬁbrogenesis by inhibiting plasmin activity [71]. Further, blockade of thrombospondin-1, an ECM protein that activates the small latent TGF- complex, prevented progression of hepatic damage and ﬁbrosis in a DMN model in vivo [89]. We used a more speciﬁc downstream blockade of the TGF- signaling pathway by overexpression of Smad7 [80]. In a rat model of bile duct ligation-induced liver ﬁbrosis, injections of an adenovirus carrying Smad7 cDNA into the portal vein during surgery and via the tail vein at later stages lead to reduced hepatic collagen expression and hydroxyproline content. In addition, -SMA staining was strongly reduced in animals treated with the Smad7 expression cassette compared to controls, indicating a signiﬁcant reduction of activated HSC in vivo. Importantly, such a beneﬁcial effect was also observed when Smad7 was expressed in animals with established ﬁbrosis. Further in vitro experiments in HSCs indicated that the underlying mechanisms most likely involve inhibition of TGF- signaling and HSC transdifferentiation. Additionally, Smad7 may also have other, yet unidentiﬁed functions, that may

Molecular Mechanisms of Alcohol-Induced Hepatic Fibrosis

also contribute to the observed effects. Therefore, further research on the details of TGF- signaling and the impact of Smad7 in the different cell types of the liver is needed to optimize treatment strategies based on Smad7. According to various experimental models, IFN- has the potential to antagonize several TGF- effects. We recently investigated the impact of IFN- on hepatic ﬁbrosis in patients with chronic hepatitis B viral infection with emphasis on IFN- signaling during activation of HSCs [90]. Histology and serum indices displayed lower ﬁbrosis scores and liver damage in the IFN- treatment group. In parallel, the number of -SMA-positive cells was strongly downregulated in patients treated with IFN-. Since it is known from other trials that IFN-, in contrast to other interferons, does not display signiﬁcant antiviral effects, we investigated the impact of this cytokine on liver ﬁbrogenesis in HSCs. Transfection of a Smad7 promoter construct and Smad7 immunoblotting showed that IFN- was able to induce Smad7 transcription and protein expression. Furthermore, our data revealed that IFN- signaling in HSCs is mediated via STAT-1 activation. Nuclear phospho-Smad2 staining was predominant in damaged tissue and absent after IFN- treatment, whereas strong cytoplasmatic Smad7 staining was only observed after IFN- application. In conclusion, our data indicate that disease-dependent TGF- signaling is abrogated by IFN- treatment. The resolution of liver ﬁbrosis correlates with an increase in HSC death [4, 91]. HSC apoptosis is associated with reduced TIMP-1 expression and has been documented during the recovery phase of experimentally induced liver injury [91]. Stellate cells also undergo spontaneous apoptosis during activation, in parallel with increased expression of death receptors of the TNF receptor superfamily and their ligands, or proapoptotic proteins, such as p53, mediating their programmed cell death [92–94]. Current treatment strategies for liver ﬁbrosis also include the selective induction of cell death in HSCs [95]. In particular, members of the TNF-receptor superfamily including TNF-, TNF-related apoptosis-inducing ligand, nerve growth factor and Fas ligand have been shown to induce cell death in HSCs [94, 96–98], but are not HSC-speciﬁc. In contrast, gliotoxin, a toxin produced by Aspergillus fumigatus, causes apoptosis in HSCs at low concentrations, but not in hepatocytes [99–101] and has been shown to reduce liver ﬁbrosis in vivo [99, 102]. Gliotoxin induces formation of ROS in HSCs, and mediates cell death via inhibition of NFB, mitochondrial permeability transition, cytochrome c release and caspase-3 activation [100, 101]. Hepatocytes are unaffected by glio-

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toxin at low concentrations due to their ability to quickly and efﬁciently metabolize the substance [101]. Recently, we have shown that anandamide, an endocannabinoid, also selectively inhibits HSC proliferation at lower concentrations and induces HSC death at higher concentrations [39]. Anandamide mediates cell death in HSCs through the interaction with membrane cholesterol, entailing an increase in intracellular ROS and inﬂux of calcium. Hepatocytes are resistant to anandamide-induced cell death due to lower binding levels compared to HSCs and due to expression of the anandamide-degrading enzyme, fatty acid amide hydrolase, which is present in HSCs only in trace amounts. We also examined the effect of TIMP-1 inactivation in hepatic ﬁbrosis through administration of a human anti-rat TIMP-1 antibody in a rat model of CCl4-induced ﬁbrosis [103]. Rats treated with the TIMP-1 antibody had reduced levels of liver ﬁbrosis compared to controls, as determined by histological analysis and hydroxyproline content. In addition, the antibody caused reductions in MMP-2 activity and -SMA expression. We also observed a reduction in the number of activated HSCs. This was presumably due to induction of apoptosis in HSCs, since TIMP-1 exerts anti-apoptotic effects in vitro and in vivo [104, 105]. Our results of this new therapeutic approach are particularly encouraging, because ﬁbrosis was established before the administration of the antibody, and rats continued to receive CCl4 simultaneously with therapy, thus better reﬂecting the clinical approach of liver ﬁbrosis treatment. Other potential candidates for molecular therapeutic approaches for ALD are summarized in Breitkopf et al. [106] and Siegmund and Brenner [107].

From Alcoholic Liver Fibrosis to Cirrhosis – Clinical Consequences

Liver cirrhosis is the end stage of ALD and is deﬁned as an irreversible remodeling of the normal liver architecture with diffuse and bridging ﬁbrosis, loss of vascular cross-sectional area and irregular nodular regeneration of hepatocellular parenchyma. The irregular hepatic architecture occurs due to: (i) the continuing hepatocellular cell death due to persistent alcohol consumption and ongoing inﬂammation; (ii) the excessive accumulation of ECM scar mass by activated HSCs; (iii) the increased hepatocellular regeneration due to the hepatocytes’ distinctive ability to proliferate, and (iv) the rearrangement of the hepatic microvasculature [2].

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Interestingly, alcoholic liver cirrhosis features mostly micronodular regeneration of hepatocellular tissue [108], also known as Laënnec’s cirrhosis (ﬁg. 1). One explanation of this morphological aspect may be the fact that ethanol actively inhibits liver regeneration by blocking the signaling cascades of growth factors, such as epidermal growth factor and insulin or by upregulating the expression of anti-proliferative and pro-ﬁbrogenic cytokines such as TGF- [109]. Ethanol withdrawal after manifestation of liver cirrhosis consequently leads to a more macronodular morphology of the cirrhotic liver [108]. Interestingly, in spite of ethanol’s effect in inhibition of hepatocyte regeneration, chronic ethanol consumption causes an increased expression of the proto-oncogene protein c-myc as well as DNA hypomethylation. Both conditions account for the higher risk of the development of hepatocellular carcinoma in alcoholic liver cirrhosis [25]. The disruption of the normal anatomy of the liver lobule by the accumulation of hepatic scar tissue in combination with the defenestration of the sinusoidal epithelial lining due to the development of manifest basal membranes in the subsinusoidal space of Dissé leads to impaired transsinusoidal exchange of substances. The result is further hepatocellular hypoxia followed by aggravated loss of hepatic parenchyma [2]. This pathophysiological mechanism applies equally to substances that are transported into the liver by the portal blood and that are released by hepatocytes into the sinusoids. Thus, the decreasing hepatic ability to detoxify noxious substances leads to their accumulation in the circulation (e.g. ammonia). The impaired ability for detoxiﬁcation may even contribute to increased ethanol toxicity during this stage of ALD, if ethanol abuse is still present. It also accounts for the decreased ability of the liver to generate and secrete indispensable metabolites (e.g. coagulation factors). Clinical consequences include hepatic encephalopathy and elevated hemorrhagic diathesis. Furthermore, the massive alterations in hepatic microcirculation caused by hepatic ﬁbrosis are a major reason for further clinical complications such as portal hypertension, formation of esophageal, gastric or rectal varices with the risk of lifethreatening hemorrhage, portal hypertensive gastropathy, ascites, and hepatorenal syndrome [110]. The pathophysiological mechanism of these complications comprises the signiﬁcant diminution of overall vascular cross-sectional area. Perisinusoidal ﬁbrosis causes narrowing or occlusion and concomitant loss of sinusoids [111, 112]. On the other hand, porto-caval shunt vessels occur during progressive ﬁbrosis that conduct the portal

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blood around the newly formed parenchymal nodules without any noticeable exchange of macromolecular metabolites [2]. Additionally, these vessels contribute to increased portal pressure [2]. Another reason for decreasing vascular capacity are activated HSCs themselves, which develop a remarkable contractile ability [10, 11, 14]. HSC contractility represents an important mechanism for the development of increasing portal resistance during liver injury. The key contractile stimulus toward stellate cells is mainly autocrine-derived endothelin (ET)-1, which also represents a highly proliferative cytokine for activated HSCs [113, 114]. Upregulation of ET-1 production is accompanied by increased endothelin-converting enzyme-1, which activates the latent ET-1 [115]. On the other hand, autocrine and paracrine mediators that are reducing portal blood pressure, such as nitric oxide and prostaglandin E2, are downregulated during ﬁbrogenesis [95, 116]. Moreover, during the development of liver cirrhosis, angiogenesis is increased with deleterious effects on hepatic hemodynamics. VEGF receptors are upregulated after injury in both sinusoidal endothelial cells and stellate cells [40, 41]. Stimulation of these receptor tyrosine kinases induces angiogenesis. In hypoxic conditions, such as ALD, both VEGF and its receptor mRNAs are rapidly induced in stellate cells, establishing an autocrine and paracrine loop supporting the development of new blood vessels [41]. It becomes evident that the molecular aspects of ﬁbrogenesis, the loss of hepatocellular function and the vascular modiﬁcations during the development of cirrhosis account for the entire development of the pathological condition. Unfortunately, the therapeutic opportunities in this ﬁnal stage are still very limited, and have to be rather symptomatic than causative [95]. In most cases, liver transplantation remains the only option left to save a patient’s life [117].

Conclusions

Alcohol abuse accounts for more than half of the prevalence of liver ﬁbrosis and cirrhosis in the Western world. Fibrosis of the liver is a wound-healing process that occurs due to persistent hepatocellular injury. Although the major mechanisms of ﬁbrogenesis are independent of the origin of liver injury, alcoholic liver ﬁbrosis features several special characteristics. An important aspect in ALD is the pronounced inﬂammatory response of Kupffer cells and other types of leukocytes (macrophages, neutrophils, lymphocytes), due to elevated gut-derived endotoxin

Molecular Mechanisms of Alcohol-Induced Hepatic Fibrosis

plasma levels. This leads to ampliﬁed formation of ROS and cell-toxic or pro-ﬁbrogenic cytokines (e.g. TNF- or TGF-1, respectively), which are together responsible for increased hepatocellular cell death and activation of HSCs, the key cell type of liver ﬁbrogenesis. HSCs change from quiescent, vitamin A-storing cells into myoﬁbroblast-like, collagen-producing cells. HSC activation is a complicated process that involves a network of diverse mediators and cell types which activate HSCs. Moreover, ethanol metabolism induces hypoxia in the pericentral region of the liver lobule causing ﬁrst hepatocellular damage and accumulation of scar tissue at this site. Ethanol metabolites, such as acetaldehyde, aldehyde-protein adducts or lipid oxidation products directly enhance HSC activation and production of ﬁbrillar collagen. If the injurious driving force, e.g. ethanol, is not withdrawn in time, the liver becomes cirrhotic. Liver cirrhosis features a remodeling of the normal liver architecture including ﬁbrosis, loss of vascular space and irregular nodular regeneration of hepatocytes. Alcoholic liver cirrhosis is mostly micronodular because of the inhibitory action of ethanol on hepatocyte growth. Destruction of the regular liver architecture accounts for the clinical consequences of liver cirrhosis. Loss of functional hepatocellular parenchyma leads to decreasing hepatic detoxiﬁcation of, e.g., ammonia, acetaldehyde or ethanol, and to impaired hepatic metabolization of, e.g., coagulation factors or albumin. Liver ﬁbrosis with built-up of basal membranes, ﬁbrotic septa and loss of sinusoidal fenestration signiﬁcantly contributes to this pathophysiological mechanism. Portal hypertension as another crucial cause of clinical complications, such as the occurrence of esophageal varices with the danger of life-threatening hemorrhage, is a consequence of the rearrangement of the hepatic vascular bed. Although withdrawal of ethanol still is the most effective intervention to prevent the manifestation of alcoholic liver cirrhosis, molecular approaches are underway that target proﬁbrogenic signal transduction in the liver or aim to induce cell death speciﬁcally in activated HSCs. For patients with cirrhosis and clinical complications, liver transplantation is currently the only curative approach.

Acknowledgements S.V.S. is supported by a grant from the Research Fund of the Faculty of Clinical Medicine Mannheim, University of Heidelberg, Germany (Formatstipendium). D.A.B. is supported by grants from the NIH. S.D. is supported by the Dietmar Hopp Foundation, Walldorf, Germany.

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15 Gressner AM, Bachem MG: Molecular mechanisms of liver ﬁbrogenesis – a homage to the role of activated fat-storing cells. Digestion 1995;56:335–346. 16 Thurman RG: II. Alcoholic liver injury involves activation of Kupffer cells by endotoxin. Am J Physiol 1998;275:G605–G611. 17 Wheeler MD, Kono H, Yin M, Nakagami M, Uesugi T, Arteel GE, Gäbele E, Rusyn I, Yamashina S, Froh M, Adachi Y, Iimuro Y, Bradford BU, Smutney OM, Connor HD, Mason RP, Goyert SM, Peters JM, Gonzalez FJ, Samulski RJ, Thurman RG: The role of Kupffer cell oxidant production in early ethanol-induced liver disease. Free Radic Biol Med 2001;31:1544–1549. 18 Thiele GM, Freeman TL, Klassen LW: Immunologic mechanisms of alcoholic liver injury. Semin Liver Dis 2004;24:273–287. 19 Kharbanda KK, Todero SL, Shubert KA, Sorrell MF, Tuma DJ: Malondialdehyde-acetaldehyde-protein adducts increase secretion of chemokines by rat hepatic stellate cells. Alcohol 2001;25:123–128. 20 Thiele GM, Duryee MJ, Willis MS, Sorrell MF, Freeman TL, Tuma DJ, Klassen LW: Malondialdehyde-acetaldehyde (MAA) modiﬁed proteins induce pro-inﬂammatory and pro-ﬁbrotic responses by liver endothelial cells. Comp Hepatol 2004;3(suppl 1):S25. 21 Maher JJ: Interactions between hepatic stellate cells and the immune system. Semin Liver Dis 2001;21:417–426. 22 Tsukamoto H: Cytokine regulation of hepatic stellate cells in liver ﬁbrosis. Alcohol Clin Exp Res 1999;23:911–916. 23 Jaeschke H, Smith CW, Clemens MG, Ganey PE, Roth RA: Mechanisms of inﬂammatory liver injury: adhesion molecules and cytotoxicity of neutrophils. Toxicol Appl Pharmacol 1996;139:213–226. 24 Paik YH, Schwabe RF, Bataller R, Russo MP, Jobin C, Brenner DA: Toll-like receptor 4 mediates inﬂammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells. Hepatology 2003;37:1043–1055. 25 Tsukamoto H, Lu SC: Current concepts in the pathogenesis of alcoholic liver injury. FASEB J 2001;15:1335–1349. 26 Wheeler MD, Kono H, Yin M, Rusyn I, Froh M, Connor HD, Mason RP, Samulski RJ, Thurman RG: Delivery of the Cu/Zn-superoxide dismutase gene with adenovirus reduces early alcohol-induced liver injury in rats. Gastroenterology 2001;120:1241–1250. 27 Wheeler MD, Nakagami M, Bradford BU, Uesugi T, Mason RP, Connor HD, Dikalova A, Kadiiska M, Thurman RG: Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J Biol Chem 2001;276:36664–36672. 28 Svegliati-Baroni G, D’Ambrosio L, Ferretti G, Casini A, Di Sario A, Salzano R, Ridolﬁ F, Saccomanno S, Jezequel AM, Benedetti A: Fibrogenic effect of oxidative stress on rat hepatic stellate cells. Hepatology 1998;27:720–726.

29 Nieto N, Greenwel P, Friedman SL, Zhang F, Dannenberg AJ, Cederbaum AI: Ethanol and arachidonic acid increase alpha 2(I) collagen expression in rat hepatic stellate cells overexpressing cytochrome P450 2E1. Role of H2O2 and cyclooxygenase-2. J Biol Chem 2000;275: 20136–20145. 30 Rojkind M, Greenwel P: Pathophysiology of liver ﬁbrosis; in Arias IM, Boyer JL, Chisari FV, Fausto N, Schachter D, Shafritz D (eds): The Liver: Biology and Pathobiology, ed 4. Philadelphia, Lippincott Williams & Wilkins, 2001, pp 721–738. 31 Lieber CS: Ethanol metabolism, cirrhosis and alcoholism. Clin Chim Acta 1997;257:59–84. 32 Nieto N, Friedman SL, Cederbaum AI: Cytochrome P450 2E1-derived reactive oxygen species mediate paracrine stimulation of collagen I protein synthesis by hepatic stellate cells. J Biol Chem 2002;277:9853–9864. 33 Nieto N, Friedman SL, Greenwel P, Cederbaum AI: CYP2E1-mediated oxidative stress induces collagen type I expression in rat hepatic stellate cells. Hepatology 1999; 30: 987– 996. 34 Nieto N, Friedman SL, Cederbaum AI: Stimulation and proliferation of primary rat hepatic stellate cells by cytochrome P450 2E1-derived reactive oxygen species. Hepatology 2002; 35: 62–73. 35 Garcia-Trevijano ER, Iraburu MJ, Fontana L, Dominguez-Rosales JA, Auster A, Covarrubias-Pinedo A, Rojkind M: Transforming growth factor beta1 induces the expression of alpha1(I) procollagen mRNA by a hydrogen peroxide-C/EBPbeta-dependent mechanism in rat hepatic stellate cells. Hepatology 1999; 29:960–970. 36 Greenwel P, Dominguez-Rosales JA, Mavi G, Rivas-Estilla AM, Rojkind M: Hydrogen peroxide: a link between acetaldehyde-elicited alpha1(I) collagen gene up-regulation and oxidative stress in mouse hepatic stellate cells. Hepatology 2000;31:109–116. 37 Bataller R, Sancho-Bru P, Gines P, Lora JM, Al-Garawi A, Sole M, Colmenero J, Nicolas JM, Jimenez W, Weich N, Gutierrez-Ramos JC, Arroyo V, Rodes J: Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II. Gastroenterology 2003;125:117–125. 38 Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA: NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic ﬁbrosis. J Clin Invest 2003; 112: 1383– 1394. 39 Siegmund SV, Uchinami H, Osawa Y, Brenner DA, Schwabe RF: Anandamide induces necrosis in primary hepatic stellate cells. Hepatology 2005;41:1085–1095.

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40 Ankoma-Sey V, Matli M, Chang KB, Lalazar A, Donner DB, Wong L, Warren RS, Friedman SL: Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing. Oncogene 1998;17:115–121. 41 Ankoma-Sey V, Wang Y, Dai Z: Hypoxic stimulation of vascular endothelial growth factor expression in activated rat hepatic stellate cells. Hepatology 2000;31:141–148. 42 Greenwel P: Acetaldehyde-mediated collagen regulation in hepatic stellate cells. Alcohol Clin Exp Res 1999;23:930–933. 43 Olynyk JK, Khan NA, Ramm GA, Brown KE, O’Neill R, Britton RS, Bacon BR: Aldehydic products of lipid peroxidation do not directly activate rat hepatic stellate cells. J Gastroenterol Hepatol 2002;17:785–790. 44 Parola M, Robino G, Marra F, Pinzani M, Bellomo G, Leonarduzzi G, Chiarugi P, Camandola S, Poli G, Waeg G, Gentilini P, Dianzani MU: HNE interacts directly with JNK isoforms in human hepatic stellate cells. J Clin Invest 1998;102:1942–1950. 45 Robino G, Parola M, Marra F, Caligiuri A, De Franco RM, Zamara E, Bellomo G, Gentilini P, Pinzani M, Dianzani MU: Interaction between 4-hydroxy-2,3-alkenals and the plateletderived growth factor-beta receptor. Reduced tyrosine phosphorylation and downstream signaling in hepatic stellate cells. J Biol Chem 2000;275:40561–40567. 46 Zamara E, Novo E, Marra F, Gentilini A, Romanelli RG, Caligiuri A, Robino G, Tamagno E, Aragno M, Danni O, Autelli R, Colombatto S, Dianzani MU, Pinzani M, Parola M: 4-Hydroxynonenal as a selective pro-ﬁbrogenic stimulus for activated human hepatic stellate cells. J Hepatol 2004;40:60–68. 47 Li J, Hu W, Baldassare JJ, Bora PS, Chen S, Poulos JE, O’Neill R, Britton RS, Bacon BR: The ethanol metabolite, linolenic acid ethyl ester, stimulates mitogen-activated protein kinase and cyclin signaling in hepatic stellate cells. Life Sci 2003;73:1083–1096. 48 Brenner DA, Waterboer T, Choi SK, Lindquist JN, Stefanovic B, Burchardt E, Yamauchi M, Gillan A, Rippe RA: New aspects of hepatic ﬁbrosis. J Hepatol 2000;32:32–38. 49 Moshage H, Casini A, Lieber CS: Acetaldehyde selectively stimulates collagen production in cultured rat liver fat-storing cells but not in hepatocytes. Hepatology 1990;12:511–518. 50 Casini A, Cunningham M, Rojkind M, Lieber CS: Acetaldehyde increases procollagen type I and ﬁbronectin gene transcription in cultured rat fat-storing cells through a protein synthesisdependent mechanism. Hepatology 1991; 13: 758–765. 51 Svegliati-Baroni G, Inagaki Y, Rincon-Sanchez AR, Else C, Saccomanno S, Benedetti A, Ramirez F, Rojkind M: Early response of alpha2(I) collagen to acetaldehyde in human hepatic stellate cells is TGF-beta independent. Hepatology 2005;42:343–352.

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52 Attard FA, Wang L, Potter JJ, Rennie-Tankersley L, Mezey E: CCAAT/enhancer binding protein beta mediates the activation of the murine alpha1(I) collagen promoter by acetaldehyde. Arch Biochem Biophys 2000;378:57–64. 53 Attard FA, Wang L, Potter JJ, Rennie-Tankersley L, Mezey E: Identiﬁcation of new sites of binding and activation of the murine alpha1(I) collagen promoter by CCAAT/enhancer binding protein beta. DNA Cell Biol 2001;20:455– 463. 54 Stefanovic B, Hellerbrand C, Holcik M, Briendl M, Liebhaber SA, Brenner DA: Posttranscriptional regulation of collagen alpha1(I) mRNA in hepatic stellate cells. Mol Cell Biol 1997;17:5201–5209. 55 Stefanovic B, Hellerbrand C, Brenner DA: Regulatory role of the conserved stem-loop structure at the 5 end of collagen alpha1(I) mRNA. Mol Cell Biol 1999;19:4334–4342. 56 Lindquist JN, Parsons CJ, Stefanovic B, Brenner DA: Regulation of alpha1(I) collagen messenger RNA decay by interactions with alphaCP at the 3-untranslated region. J Biol Chem 2004;279:23822–23829. 57 Stefanovic B, Stefanovic L, Schnabl B, Bataller R, Brenner DA: TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b and is necessary for collagen type I synthesis. Mol Cell Biol 2004;24:1758–1768. 58 Stefanovic B, Brenner DA: 5 Stem-loop of collagen alpha 1(I) mRNA inhibits translation in vitro but is required for triple helical collagen synthesis in vivo. J Biol Chem 2003;278:927– 933. 59 Arthur MJ: Collagenases and liver ﬁbrosis. J Hepatol 1995;22:43–48. 60 Arthur MJ, Mann DA, Iredale JP: Tissue inhibitors of metalloproteinases, hepatic stellate cells and liver ﬁbrosis. J Gastroenterol Hepatol 1998;13(suppl):S33–S38. 61 Arthur MJ, Iredale JP, Mann DA: Tissue inhibitors of metalloproteinases: role in liver ﬁbrosis and alcoholic liver disease. Alcohol Clin Exp Res 1999;23:940–943. 62 Arthur MJ: Fibrogenesis II. Metalloproteinases and their inhibitors in liver ﬁbrosis. Am J Physiol Gastrointest Liver Physiol 2000; 279: G245–G249. 63 Benyon RC, Arthur MJ: Extracellular matrix degradation and the role of hepatic stellate cells. Semin Liver Dis 2001;21:373–384. 64 Rojkind M: Role of metalloproteinases in liver ﬁbrosis. Alcohol Clin Exp Res 1999; 23: 934– 939. 65 Benyon RC, Hovell CJ, Da Gaca M, Jones EH, Iredale JP, Arthur MJ: Progelatinase A is produced and activated by rat hepatic stellate cells and promotes their proliferation. Hepatology 1999;30:977–986. 66 Wells RG: Fibrogenesis. V. TGF-beta signaling pathways. Am J Physiol Gastrointest Liver Physiol 2000;279:G845–G850. 67 Branton MH, Kopp JB: TGF-beta and ﬁbrosis. Microbes Infect 1999;1:1349–1365. 68 Border WA, Noble NA: Transforming growth factor beta in tissue ﬁbrosis. N Engl J Med 1994;331:1286–1292.

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69 Kim Y, Ratziu V, Choi SG, Lalazar A, Theiss G, Dang Q, Kim SJ, Friedman SL: Transcriptional activation of transforming growth factor beta1 and its receptors by the Krüppel-like factor Zf9/core promoter-binding protein and Sp1. Potential mechanisms for autocrine ﬁbrogenesis in response to injury. J Biol Chem 1998;273:33750–33758. 70 Kojima S, Hayashi S, Shimokado K, Suzuki Y, Shimada J, Crippa MP, Friedman SL: Transcriptional activation of urokinase by the Krüppel-like factor Zf9/COPEB activates latent TGF-beta1 in vascular endothelial cells. Blood 2000;95:1309–1316. 71 Okuno M, Akita K, Moriwaki H, Kawada N, Ikeda K, Kaneda K, Suzuki Y, Kojima S: Prevention of rat hepatic ﬁbrosis by the protease inhibitor, camostat mesilate, via reduced generation of active TGF-beta. Gastroenterology 2001;120:1784–1800. 72 Breitkopf K, Lahme B, Tag CG, Gressner AM: Expression and matrix deposition of latent transforming growth factor beta binding proteins in normal and ﬁbrotic rat liver and transdifferentiating hepatic stellate cells in culture. Hepatology 2001;33:387–396. 73 Breitkopf K, Sawitza I, Westhoff JH, Wickert L, Dooley S, Gressner AM: Thrombospondin 1 acts as a strong promoter of transforming growth factor beta effects via two distinct mechanisms in hepatic stellate cells. Gut 2005; 54:673–681. 74 Gong W, Roth S, Michel K, Gressner AM: Isoforms and splice variant of transforming growth factor beta-binding protein in rat hepatic stellate cells. Gastroenterology 1998;114: 352–363. 75 Roth S, Gong W, Gressner AM: Expression of different isoforms of TGF-beta and the latent TGF-beta binding protein (LTBP) by rat Kupffer cells. J Hepatol 1998;29:915–922. 76 Roulot D, Sevcsik AM, Coste T, Strosberg AD, Marullo S: Role of transforming growth factor beta type II receptor in hepatic ﬁbrosis: studies of human chronic hepatitis C and experimental ﬁbrosis in rats. Hepatology 1999;29:1730– 1738. 77 Dooley S, Delvoux B, Lahme B, MangasserStephan K, Gressner AM: Modulation of transforming growth factor beta response and signaling during transdifferentiation of rat hepatic stellate cells to myoﬁbroblasts. Hepatology 2000;31:1094–1106. 78 Dooley S, Streckert M, Delvoux B, Gressner AM: Expression of Smads during in vitro transdifferentiation of hepatic stellate cells to myoﬁbroblasts. Biochem Biophys Res Commun 2001;283:554–562. 79 Dooley S, Delvoux B, Streckert M, Bonzel L, Stopa M, ten Dijke P, Gressner AM: Transforming growth factor beta signal transduction in hepatic stellate cells via Smad2/3 phosphorylation, a pathway that is abrogated during in vitro progression to myoﬁbroblasts. TGFbeta signal transduction during transdifferentiation of hepatic stellate cells. FEBS Lett 2001; 502: 4–10.

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80 Dooley S, Hamzavi J, Breitkopf K, Wiercinska E, Said HM, Lorenzen J, Ten Dijke P, Gressner AM: Smad7 prevents activation of hepatic stellate cells and liver ﬁbrosis in rats. Gastroenterology 2003;125:178–191. 81 Stopa M, Benes V, Ansorge W, Gressner AM, Dooley S: Genomic locus and promoter region of rat Smad7, an important antagonist of TGFbeta signaling. Mamm Genome 2000;11:169– 176. 82 Furukawa F, Matsuzaki K, Mori S, Tahashi Y, Yoshida K, Sugano Y, Yamagata H, Matsushita M, Seki T, Inagaki Y, Nishizawa M, Fujisawa J, Inoue K: p38 MAPK mediates ﬁbrogenic signal through Smad3 phosphorylation in rat myoﬁbroblasts. Hepatology 2003; 38: 879–889. 83 Schnabl B, Kweon YO, Frederick JP, Wang XF, Rippe RA, Brenner DA: The role of Smad3 in mediating mouse hepatic stellate cell activation. Hepatology 2001;34:89–100. 84 Uemura M, Swenson ES, Gaca MD, Giordano FJ, Reiss M, Wells RG: Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization. Mol Biol Cell 2005;16:4214–4224. 85 Chen A: Acetaldehyde stimulates the activation of latent transforming growth factor-beta1 and induces expression of the type II receptor of the cytokine in rat cultured hepatic stellate cells. Biochem J 2002;368:683–693. 86 Anania FA, Potter JJ, Rennie-Tankersley L, Mezey E: Activation by acetaldehyde of the promoter of the mouse alpha2(I) collagen gene when transfected into rat activated stellate cells. Arch Biochem Biophys 1996; 331: 187– 193. 87 Qi Z, Atsuchi N, Ooshima A, Takeshita A, Ueno H: Blockade of type beta transforming growth factor signaling prevents liver ﬁbrosis and dysfunction in the rat. Proc Natl Acad Sci USA 1999;96:2345–2349. 88 Ueno H, Sakamoto T, Nakamura T, Qi Z, Astuchi N, Takeshita A, Shimizu K, Ohashi H: A soluble transforming growth factor beta receptor expressed in muscle prevents liver ﬁbrogenesis and dysfunction in rats. Hum Gene Ther 2000;11:33–42. 89 Kondou H, Mushiake S, Etani Y, Miyoshi Y, Michigami T, Ozono K: A blocking peptide for transforming growth factor-beta1 activation prevents hepatic ﬁbrosis in vivo. J Hepatol 2003;39:742–748. 90 Weng H, Wang B, Jia J, Wu W, Xian J, Gressner AM, Mertens PR, Cai W, Dooley S: Hepatic ﬁbrosis in patients with chronic hepatitis B virus infection can be partially reversed by IFN-. Clin Gastroenterol Hepatol 2005; in press. 91 Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, Hovell C, Arthur MJ: Mechanisms of spontaneous resolution of rat liver ﬁbrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998;102:538– 549.

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92 Gressner AM: The cell biology of liver ﬁbrogenesis – an imbalance of proliferation, growth arrest and apoptosis of myoﬁbroblasts. Cell Tissue Res 1998;292:447–452. 93 Iredale JP: Hepatic stellate cell behavior during resolution of liver injury. Semin Liver Dis 2001;21:427–436. 94 Saile B, Knittel T, Matthes N, Schott P, Ramadori G: CD95/CD95L-mediated apoptosis of the hepatic stellate cell. A mechanism terminating uncontrolled hepatic stellate cell proliferation during hepatic tissue repair. Am J Pathol 1997;151:1265–1272. 95 Bataller R, Brenner DA: Hepatic stellate cells as a target for the treatment of liver ﬁbrosis. Semin Liver Dis 2001;21:437–451. 96 Lang A, Schoonhoven R, Tuvia S, Brenner DA, Rippe RA: Nuclear factor kappaB in proliferation, activation, and apoptosis in rat hepatic stellate cells. J Hepatol 2000; 33: 49– 58. 97 Taimr P, Higuchi H, Kocova E, Rippe RA, Friedman S, Gores GJ: Activated stellate cells express the TRAIL receptor-2/death receptor-5 and undergo TRAIL-mediated apoptosis. Hepatology 2003;37:87–95. 98 Trim N, Morgan S, Evans M, Issa R, Fine D, Afford S, Wilkins B, Iredale J: Hepatic stellate cells express the low afﬁnity nerve growth factor receptor p75 and undergo apoptosis in response to nerve growth factor stimulation. Am J Pathol 2000;156:1235–1243. 99 Wright MC, Issa R, Smart DE, Trim N, Murray GI, Primrose JN, Arthur MJ, Iredale JP, Mann DA: Gliotoxin stimulates the apoptosis of human and rat hepatic stellate cells and enhances the resolution of liver ﬁbrosis in rats. Gastroenterology 2001;121:685–698. 100 Kweon YO, Paik YH, Schnabl B, Qian T, Lemasters JJ, Brenner DA: Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J Hepatol 2003;39:38–46. 101 Orr JG, Leel V, Cameron GA, Marek CJ, Haughton EL, Elrick LJ, Trim JE, Hawksworth GM, Halestrap AP, Wright MC: Mechanism of action of the antiﬁbrogenic compound gliotoxin in rat liver cells. Hepatology 2004;40:232–242. 102 Dekel R, Zvibel I, Brill S, Brazovsky E, Halpern Z, Oren R: Gliotoxin ameliorates development of ﬁbrosis and cirrhosis in a thioacetamide rat model. Dig Dis Sci 2003; 48: 1642–1647. 103 Parsons CJ, Bradford BU, Pan CQ, Cheung E, Schauer M, Knorr A, Krebs B, Kraft S, Zahn S, Brocks B, Feirt N, Mei B, Cho MS, Ramamoorthi R, Roldan G, Ng P, Lum P, Hirth-Dietrich C, Tomkinson A, Brenner DA: Antiﬁbrotic effects of a tissue inhibitor of metalloproteinase-1 antibody on established liver ﬁbrosis in rats. Hepatology 2004; 40:1106–1115.

104 Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Nakatani T, Tsujinoue H, Yanase K, Namisaki T, Imazu H, Fukui H: Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver ﬁbrosis resolution in the transgenic mouse. Hepatology 2002;36:850– 860. 105 Murphy FR, Issa R, Zhou X, Ratnarajah S, Nagase H, Arthur MJ, Benyon C, Iredale JP: Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver ﬁbrosis. J Biol Chem 2002;277:11069–11076. 106 Breitkopf K, Haas S, Wiercinska E, Singer MV, Dooley S: Anti-TGF-beta strategies for the treatment of chronic liver disease. Alcohol Clin Exp Res 2005;29(11 suppl):121S– 131S. 107 Siegmund SV, Brenner DA: Molecular pathogenesis of alcohol-induced hepatic ﬁbrosis. Alcohol Clin Exp Res 2005;29(11 suppl): 102S–109S. 108 Goodman Z, Ishak K: Hepatic histopathology; in Schiff E, Sorrell MF, Maddrey WC (eds): Schiff’s Diseases of the Liver, ed 8. Philadelphia, Lippincott-Raven, 1999, vol 1, pp 53–117. 109 Diehl A, Rai R: Liver regeneration; in Schiff E, Sorrell MF, Maddrey WC (eds): Schiff’s Diseases of the Liver, ed 8. Philadelphia, Lippincott-Raven, 1999, vol 1, pp 39–52. 110 Bosch J, Navasa M, Garcia-Pagan JC, DeLacy AM, Rodes J: Portal hypertension. Med Clin North Am 1989;73:931–953. 111 Vollmar B, Wolf B, Siegmund S, Katsen AD, Menger MD: Lymph vessel expansion and function in the development of hepatic ﬁbrosis and cirrhosis. Am J Pathol 1997;151:169– 175. 112 Vollmar B, Siegmund S, Richter S, Menger MD: Microvascular consequences of Kupffer cell modulation in rat liver ﬁbrogenesis. J Pathol 1999;189:85–91. 113 Rockey D: The cellular pathogenesis of portal hypertension: stellate cell contractility, endothelin, and nitric oxide. Hepatology 1997;25: 2–5. 114 Rockey DC, Fouassier L, Chung JJ, Carayon A, Vallee P, Rey C, Housset C: Cellular localization of endothelin-1 and increased production in liver injury in the rat: potential for autocrine and paracrine effects on stellate cells. Hepatology 1998;27:472–480. 115 Shao R, Yan W, Rockey DC: Regulation of endothelin-1 synthesis by endothelin-converting enzyme-1 during wound healing. J Biol Chem 1999;274:3228–3234. 116 Rockey DC: Hepatic blood ﬂow regulation by stellate cells in normal and injured liver. Semin Liver Dis 2001;21:337–349. 117 Albanis E, Safadi R, Friedman SL: Treatment of hepatic ﬁbrosis: almost there. Curr Gastroenterol Rep 2003;5:48–56.

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mining the need for speciﬁc therapy in patients with severe AH, and (2) determining the need for liver transplantation in patients with alcoholic cirrhosis. Alcoholic Hepatitis The prognosis of individual patients with AH can vary dramatically. Patients with severe disease have an extremely high mortality, approaching that of patients with fulminant hepatic failure. Clinical features associated with severe disease include hepatic encephalopathy, marked prolongation of prothrombin time values, elevation in serum bilirubin above 25 mg/dl, depressed serum albumin, elevated serum creatinine, and older age. Maddrey et al. [8] discovered a simple formula called the discriminant function (DF) ([4.6 ! prothrombin time – control value (seconds)] + serum bilirubin (mg/dl)) that is extremely useful in identifying patients with poor shortterm survival. Three prospective studies have demonstrated that patients with DF values of 132 have an extremely poor prognosis, with 1-month mortality rates of 35–45% [9–11]. In contrast, patients with lower DF values have short-term survival rates of 90–100% [8, 12]. Other important prognostic variables in patients with severe AH are the presence of spontaneous hepatic encephalopathy and hepatorenal syndrome [9, 13, 14]. Onemonth mortality in patients with spontaneous hepatic encephalopathy is approximately 50% and in those with hepatorenal syndrome is 75% [9–11, 13, 14]. Alcoholic Cirrhosis The clinical tool most widely used to determine prognosis in patients with alcoholic cirrhosis is the Child-Turcotte-Pugh (CTP) classiﬁcation. This simple classiﬁcation system, which was designed to stratify the risk of portacaval shunt surgery in cirrhotics with variceal bleeding, has gained favor over the past decade as a rapid method for determining the prognosis of patients with various chronic liver diseases. The CTP is as effective as quantitative liver function tests and disease-speciﬁc prognostic models in determining short-term prognosis in groups of patients awaiting liver transplantation [15, 16]. Although its limitations have been well described, the CTP has been widely adopted for risk-stratifying patients with cirrhosis because of its simplicity and ease of use. Five-year survival rates of patients with alcoholic cirrhosis vary dramatically by CTP classiﬁcation at the time of clinical presentation [17]. The development of ascites, variceal bleeding, hepatic encephalopathy, spontaneous bacterial peritonitis (SBP), or hepatorenal syndrome also has a signiﬁcant impact on

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the prognosis of patients with alcoholic cirrhosis. The 5year survival of individuals who develop any of these complications is only 20–50% of that for patients with compensated cirrhosis [18]. The most ominous complications are SBP and rapid-onset hepatorenal syndrome. Less than half of those who develop SBP can be expected to survive 1 year, while the median survival of patients with hepatorenal syndrome is less than 2 weeks [19, 20]. Other models that have been used to predict prognosis in patients with alcoholic cirrhosis are the proportionalhazards model developed by Poynard et al. [16, 17] (Beclere model) and the prognostic model for end-stage liver disease (MELD) developed by investigators at the Mayo Clinic [21]. The Beclere model, which was developed from a database of 818 patients with alcoholic cirrhosis who were followed prospectively for 4 years, includes serum bilirubin, serum albumin, patient age, and hepatic encephalopathy [16, 17]. The MELD model, which was originally developed to assess short-term prognosis in patients undergoing transjugular intrahepatic portosystemic shunts, includes serum creatinine, the international normalized ratio for prothrombin time, and serum bilirubin values [21]. A modiﬁcation of this model is now used to prioritize patients for donor allocation in the United States. The MELD score has been shown to be useful in predicting short-term survival in groups of patients with various liver diseases [22].

Therapy for ALD

Unfortunately, in the United States there is no FDAapproved therapy for either alcoholic cirrhosis or AH. However, several therapies have been employed to either treat the complications of ALD or, in some cases, attempt to treat the liver damage itself. We will discuss therapies available for which there are data from large randomized human studies, as well as selected promising new approaches based on results from basic research studies. Treatment of Decompensation In the absence of hepatocellular carcinoma, death due to ALD is often secondary to the disease per se. As mentioned above, there is a host of effects associated with a failing liver (e.g., portal hypertension, hepatic encephalopathy, ascites, hepatorenal syndrome, and esophageal varices) that are the major causes of clinical complications and mortality in ALD. These complications may be due to liver failure and portal hypertension or to factors

Bergheim /McClain /Arteel

Anorexia Encaphalopathy Energy expenditure

Fever Neutrophilia

Portal vein thrombosis Muscle wasting Liver injury Altered amino acid metabolism

Triglycerides

Collagen formation

Delayed gastric emptying Gut permeability

Altered mineral metabolism ( zinc)

Hypoalbuminemia

Osteoporosis

Endothelial permeability with edema formation

Fig. 1. Selected clinical complications of ALD in which TNF may play a role.

such as tumor necrosis factor (TNF) that play an etiologic role in the liver disease (ﬁg. 1). These complications are very common in alcoholic cirrhotics. For example, Lucena et al. [23] showed incidence rates for ascites, hepatic encephalopathy and variceal bleeding of 49, 24 and 22%, respectively, in cirrhotic patients in a multicenter study in Spain. Powell and Klatskin [24] showed that 5year survival in ALD patients with overt hepatic decompensation (drinkers/abstainers) was 34 and 60%, respectively; in contrast, compensated cirrhotics (drinkers/ abstainers) had a 5-year survival of 68 and 89%, respectively. Therefore, clinical management of these complications of cirrhosis is critical for the long-term survival of the patient [25–28].

death, Merkel et al. [29] showed that the cumulative probability of survival was 87% in persistent abstainers and only 55% in persistent drinkers. Moreover, recent data from recent Veterans Administration (VA) Cooperative Studies suggest that reducing, but not stopping, ethanol consumption also improves projected survival in ALD [30]. Thus, abstinence, or a major reduction in drinking, should be encouraged in all patients with ALD. Individual patients may exhibit major clinical improvement with abstinence (ﬁg. 2). Newer agents to improve abstinence, such as Naltrexone and Acamprosate, have been shown to have efﬁcacy in some chronic alcoholics, however there are no large multicenter studies evaluating these drugs in patients with ALD.

Abstinence Abstinence from alcohol is vital in order to prevent further ongoing liver injury, ﬁbrosis and possibly hepatocellular carcinoma. Abstinence causes total resolution of alcoholic steatosis. There are limited studies evaluating the effects of abstinence from alcohol on the progression of ALD, and these are retrospective, non-randomized trials. However, virtually all studies show the beneﬁcial effects of abstinence. As mentioned above, early studies from the program of Powell and Klatskin [24] showed that patients with jaundice or ascites especially beneﬁted from abstinence. In a recent small series of patients with alcoholic cirrhosis who were followed for 4 years or until

Nutrition Therapy Alcoholic Hepatitis Malnutrition is prevalent in liver disease, especially in the more severe forms of chronic liver disease. The etiology of this malnutrition is multifactorial (table 1). Probably the most extensive studies on the nutritional status of patients with liver disease are large studies by the VA Cooperative Studies Program dealing with patients having AH [31]. The ﬁrst of these studies demonstrated that virtually every patient with AH had some degree of malnutrition [32]. Patients had a mean alcohol consumption of 228 g/day (with almost 50% of energy intake coming from alcohol). The severity of liver disease generally cor-

Treatment of Alcoholic Liver Disease

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Fig. 2. Patient with alcoholic cirrhosis before and after 3 years of abstinence.

Table 1. Selected causes of malnutrition

Anorexia Altered taste/smell Nausea/vomiting Diarrhea/malabsorption Poor food availability/quality Metabolic disturbances (e.g., hypermetabolism/catabolism) Cytokine effects Complications of liver disease (PSE, ascites, GI bleeding) Unpalatible diets (Na, protein) Fasting for procedures PSE = Partial splenic embolization; GI = gastrointestinal.

related with the severity of malnutrition. Similar data were generated in a follow-up VA study on AH (No. 275). In both of these studies, patients were given a balanced 2,500-kcal hospital diet, monitored carefully by a dietitian, and were encouraged to consume the diet. In the second study, patients in the therapy arm of the protocol also received an enteral nutritional support product high in branched-chain amino acids as well as the anabolic steroid oxandrolone (80 mg/day). Patients were not fed by tube if voluntary oral intake was inadequate in either study (probably a study design ﬂaw, in retrospect). Voluntary oral food intake correlated in a stepwise fashion with 6-month mortality data. Thus, patients who volun-

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tarily consumed 13,000 kcal/day had virtually no mortality, whereas those consuming !1,000 kcal/day had a 180% 6-month mortality [31]. Moreover, the degree of malnutrition correlated with the development of serious complications such as encephalopathy, ascites and hepatorenal syndrome [31]. Cirrhosis Interest in nutrition therapy for cirrhosis was stimulated when Patek et al. [33] and demonstrated that a nutritious diet improved the 5-year outcome of patients with alcoholic cirrhosis compared with patients consuming an inadequate diet. Several recent studies have further supported the concept of improved outcome with nutritional support in patients with cirrhosis. Hirsch et al. [34] demonstrated that outpatients taking an enteral nutritional support product (1,000 kcal, 34 g protein) had signiﬁcantly improved protein intake and signiﬁcantly fewer hospitalizations. These same investigators subsequently gave an enteral supplement to outpatients with alcoholic cirrhosis and observed an improvement in nutritional status and immune function [35]. In the VA Cooperative Study No. 275 on nutritional support in ALD using both an anabolic steroid and an enteral nutritional supplement, improved mortality was seen with the combination of oxandrolone plus supplement in patients who had moderate protein-energy malnutrition [31]. Those with severe malnutrition did not signiﬁcantly beneﬁt from therapy, possibly because their malnutrition was so

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advanced that no intervention, including nutrition, could help. Studies by Kearns et al. [36] showed that patients with ALD hospitalized for treatment and given an enteral nutritional supplement via tube feeding had signiﬁcantly improved serum bilirubin levels and liver function as assessed by antipyrine clearance. Moreover, a major randomized multicenter study of enteral nutrition versus steroids in patients with AH showed similar overall initial outcomes, and less long-term infections in the nutrition group [10]. Thus, traditional nutritional supplementation clearly improves nutritional status and, in some instances, hepatic function and other outcome indicators in AH/cirrhosis. Drug Therapies of Likely Beneﬁt Corticosteroids Corticosteroids have been the most extensively studied form of therapy for AH, but their role remains limited [37]. The rationale for steroid use is to decrease the immune response and pro-inﬂammatory cytokine response. Most randomized studies have supported the use of corticosteroids in moderate/severe AH [38], but the large multicenter VA study by Mendenhall et al. [31] yielded negative results. Most meta-analyses support the use of steroids for severe acute AH including the most recent study by Mathurin et al. [12]. This study reported signiﬁcantly improved survival at 28 days (85 vs. 65%) in severely ill AH patients having a DF of 132. This survival advantage may extend to 1 year, but not 2. Independent prognostic factors associated with death at 28 days in this meta-analysis were steroid treatment, age, and creatinine. It is important to note that the patients studied were highly selected, and infections (e.g., SBP), gastrointestinal bleeding, and many other common complications were exclusions for entry into these studies. Most investigators agree that if corticosteroids are to be used, they should be reserved for those with relatively severe liver disease (DF 132), and possibly those with hepatic encephalopathy. Steroids have well-documented side effects, including enhancing the risk of infection which is already substantial in patients with AH. Thus, a major disadvantage to corticosteroids is their lack of applicability in many patients with AH.

cytokines including TNF. Akriviadis et al. [9] from the University of Southern California Liver Unit performed a prospective, randomized, double-blind clinical trial of PTX in severe AH (DF 132). Forty-nine patients received 400 mg PTX orally 3 times daily and 52 received placebo (vitamin B12) for 4 weeks. PTX treatment improved survival. Twelve PTX patients died (24.5%) compared with 24 (46%) placebo patients. PTX also decreased hepatorenal syndrome as a cause of death. Six of the 12 (50%) PTX-treated patients who died did so of renal failure compared with 22 of the 24 (92%) control patients who died of renal failure. Multivariate analysis revealed age, serum creatinine at randomization, and treatment with PTX as independent factors associated with survival. We regularly use PTX in patients with AH and alcoholic cirrhosis because of its anti-inﬂammatory properties, its protective effects against hepatorenal syndrome, and its excellent safety proﬁle.

Pentoxifylline Pentoxifylline (PTX) is a nonselective phosphodiesterase inhibitor which increases intracellular concentrations of adenosine 3,5-cyclic monophosphate (cAMP) and guanosine 3,5-cyclic monophosphate (cGMP), and decreases production of pro-inﬂammatory chemokines/

Anti-TNF Therapy Dysregulated cytokine metabolism was described in AH long before it was recognized in inﬂammatory bowel disease and rheumatoid arthritis. However, anti-TNF therapy has been an FDA-approved, highly effective treatment for both of these diseases for several years. An initial concern in ALD arose from early observations that low ‘basal’ amounts of TNF were important for liver regeneration [39]. Thus, many investigators took the tack that downregulating but not totally blocking TNF activity would be a preferred therapeutic intervention. Indeed, many therapies used in ALD (corticosteroids, PTX, Sadenosylmethionine, etc.) decrease but do not abolish TNF activity. Because anti-TNF antibody has been shown to block development of alcohol-induced liver injury in rats, it is now being used in small clinical trials in patients with AH. A study from Europe involved 12 patients with moderate to severe AH who were given Inﬂiximab (anti-TNF antibody) 5 mg/kg as a single 2-hour infusion. Ten of the 12 patients were alive at a median of 15 months [40]. Pilot data from a small US open-label trial of etanercept, a TNF receptor antagonist, also showed safety in patients with less severe AH, and a multicenter trail studying this agent is being funded by the National Institutes of Health [41]. On the other hand, a large double-blind randomized control trial from France using either prednisolone treatment or prednisolone treatment plus high-dose Inﬂiximab in patients with acute AH was terminated due to increased infectious complications in the combined therapy group [40]. Thus, etanercept may be more attractive

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than Inﬂiximab in ALD because of its shorter duration of action. However, there remains the theoretic concern of completely blocking TNF activity over a long duration in relation to increased infections and impaired liver regeneration. On a related point, the question of whether or not anti-TNF therapies will be beneﬁcial for cirrhosis as well as AH remains to be determined. Until more data are available, speciﬁc anti-TNF therapy should optimally be performed in the context of a clinical trial [41]. Drug Therapies of Unlikely Beneﬁt Colchicine Colchicine has been suggested as a treatment for ALD because of its anti-ﬁbrotic effects. It has many potential therapeutic mechanisms of action including inhibition of collagen production, enhancement of collagenase activity, and anti-inﬂammatory functions. Initial positive studies by Kershenobich et al. [42] led to a large VA Cooperative Study evaluating colchicine therapy in alcoholic cirrhosis that has recently been completed. Results showed no beneﬁcial effect on either overall mortality or liver-related mortality [43]. A recent smaller study from Europe also showed no beneﬁcial effects of colchicine [44]. Thus, despite initial enthusiasm and biochemical rationale for use of this drug, it does not appear to be effective in ALD.

However, a recently completed VA Cooperative Study failed to show signiﬁcant beneﬁt in human ALD [30]. It should be noted that in that study, the partial abstinence observed in all patients, regardless of whether or not they received placebo or drug, may have confounded any possible protective effects (see Abstinence above) [30]. Anabolic Steroids ALD is associated with severe muscle wasting. While in part mediated by nutritional deﬁciencies, decreased functional levels of anabolic and androgenic steroids in alcoholics also occur [47], which may contribute to the loss of muscle mass. Utilizing the Cochrane database [48], the results of 5 randomized clinical trials on 499 patients with AH and/or cirrhosis demonstrated no signiﬁcant effects of anabolic-androgenic steroids on mortality, liverrelated mortality, and liver histology. There was also no effect of anabolic-androgenic steroids on a number of other outcome measures. Furthermore, a slight increase in the risk of occurrence of serious adverse events was observed with the use of these hormones. Thus, the lack of any observed beneﬁt coupled with potential iatrogenic effects decreases enthusiasm for the use of these hormones in ALD.

Propylthiouracil (PTU) Chronic alcohol feeding in experimental animals produces a hypermetabolic state with increased oxygen consumption. This may lead to relative hypoxia, especially in the central lobular area, or zone 3, of the liver. PTU has been postulated to attenuate this hypermetabolic state, to function as an antioxidant, and to improve portal blood ﬂow. This prompted a long-term study of PTU therapy by Orrego et al. [1] in over 300 patients with a variety of types of liver disease, including ALD. In the total study population, mortality was reduced by nearly 50% in patients receiving PTU [1]. A recent Cochran review evaluated PTU therapy for ALD, including alcoholic steatosis, alcoholic ﬁbrosis, AH and/or cirrhosis [45]. Combining the results of 6 randomized clinical trials which included 710 patients, no signiﬁcant effects of PTU versus placebo on mortality or liver-related mortality, complications of liver disease, or liver histology were shown [45].

Complementary and Alternative Medicines Silymarin (Milk Thistle) Silymarin is probably the most widely used form of complementary and alternative medicine in the treatment of liver disease in the US. It has antioxidant activities, it protects against lipid peroxidation, and it has antiinﬂammatory and anti-ﬁbrotic effects. Large controlled trials of silymarin have been performed in Europe, with varying results. Ferenci et al. [49] evaluated 170 patients with cirrhosis in a treatment program (140 mg t.i.d.) with a mean duration of 41 months. They observed a positive beneﬁcial effect, especially in patients with alcoholic cirrhosis and in those with milder disease (Child’s A category). On the other hand, a study by Pares et al. [50] found no beneﬁcial effects (150 mg silymarin t.i.d.) in a study of 200 patients with alcoholic cirrhosis, some of whom also had hepatitis C. Both of these trials had major shortcomings, including high dropout rates and compliance issues. In all studies performed thus far, the drug appears quite safe.

Dilinoleoylphosphatidylcholine Dilinoleoylphosphatidylcholine (a form of lecithin/ soybean extract) has antioxidant, anti-ﬁbrotic, and anticytokine activity in experimental rat models of ALD [46].

S-Adenosylmethionine (SAMe) SAMe, or AdoMet, is an obligatory intermediate in the conversion of methionine to cysteine in the hepatic transsulfuration pathway. SAMe is a precursor for syntheses

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of polyamines, choline, and glutathione (GSH), and it is the major methylating agent for a vast number of molecules via speciﬁc methyltransferases [51]. Patients with ALD have elevated plasma methionine levels, markedly delayed clearance of an oral methionine load, and decreased hepatic methionine adenosyltransferase (MAT) activity (the enzyme responsible for conversion of methionine to SAMe). Hepatic-speciﬁc MAT is highly sensitive to oxidative stress, and it is likely that subnormal hepatic MAT activity reported in ALD is due to oxidation of the active site [52]. Studies from our laboratories have shown that SAMe downregulates production of the cytotoxic pro-inﬂammatory cytokine, TNF, in animal models of liver injury and in peripheral blood monocytes or macrophage cell lines in vitro [53, 54]. Mato et al. [55] reported that patients with alcoholic liver cirrhosis who were randomized to receive SAMe (1,200 mg/day orally) for 2 years had decreased liver mortality/liver transplantation (16 vs. 30%) compared to the placebo-treated group. Vitamin E Vitamin E deﬁciency has been well documented in ALD [56]. Vitamin E has been used extensively with hepatoprotective effects in experimental models of liver injury such as that induced by carbon tetrachloride or ischemia. Vitamin E has multiple potential beneﬁcial effects including membrane stabilization [56], reduced NFB activation and TNF production [57], and inhibition of hepatic stellate cell activation and collagen production [58]. Unfortunately, a major randomized study of vitamin E in ALD showed no beneﬁt, but may have used an inadequate dose (500 mg) [59]. A smaller study with a higher dose (1,000 mg) of vitamin E in AH observed some normalization of serum hyaluronic acid levels, but without signiﬁcant changes in indices of liver damage [60]. Furthermore, recent meta-analyses suggest that high-dose vitamin E supplementation is associated with an increase in overall mortality [61, 62], raising concerns of prolonged usage of this drug in humans. It should be noted that most clinical trials with vitamin E have been performed in the absence of concomitant citamin C (ascorbic acid) supplementation, which is required for catalytic maintenance of the antioxidant function of vitamin E.

MET

Ethanol

(– )

S M

T M BH

(– )

( – ) Ethanol M A

T

Ethanol HC

Betaine

SAMe CO

Choline

S AH

Fig. 3. Effect of ethanol on methionine metabolism.

GSH prodrug, N-acetylcysteine (given as Mucomyst), is the standard therapy for acetaminophen toxicity in humans. Maintaining adequate hepatocyte GSH levels has been documented to prevent acetaminophen liver injury. GSH prodrugs can directly affect the hepatocyte, and they can also positively modulate pro-inﬂammatory cytokine production with inhibition of cytokines such as TNF and IL-8 [57]. Pena et al. [64] demonstrated that the GSH prodrug, procysteine, can increase whole blood GSH and inhibit monocyte TNF and IL-8 production when given intravenously to stable alcoholic cirrhotics. Similarly, procysteine was shown to protect against alcohol-induced liver injury in the intragastric ethanol-feeding model [65]. However, large, randomized studies of GSH prodrugs using mortality as an outcome indicator are lacking in ALD.

GSH Prodrugs GSH is a tripeptide which is synthesized from glutamate, cysteine, and glycine. GSH prodrugs have been used extensively in virtually every known experimental model of hepatotoxicity with beneﬁcial results [63]. The

Other Selected Potential Therapies As mentioned above, alcohol alters methionine metabolism in the liver. In addition to increasing methionine and decreasing SAMe levels, there is an accumulation of homocysteine after alcohol exposure (ﬁg. 3) [66, 67]. In human alcoholics, the mRNA levels of the 2 enzymes responsible for remethylation of homocysteine, methylfolate-homocysteine methyltransferase (methionine synthase) and betaine-homocysteine methyltransferase are decreased [68]. Furthermore, levels of precursors required for remethylation of homocysteine (e.g. fo-

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late and vitamin B12) are also decreased in alcoholics [67]. For this reason, it has been proposed that supplementation with either folic acid [69] or betaine may also be protective in ALD. Indeed, experimental liver damage in both rats and mice is protected by betaine supplementation [70]. While much of the hypothesized protective effect of betaine has focused on decreasing homocysteine levels, recent work by Song et al. [71] indicates that Sadenosyl homocysteine may contribute the sensitization of hepatocytes to TNF-induced cell killing. Another potential dietary supplement is zinc. It is well known that circulating levels of zinc are depleted in patients with AH and cirrhosis [72, 73]. The zinc depletion caused by alcohol consumption appears to be mediated both at the level of absorption and excretion [74, 75]. Further, in animal models of alcohol-induced liver damage, zinc supplementation prevented liver damage, oxidative stress and inﬂammatory cytokine (TNF) production caused by alcohol feeding [76]. Zinc also prevented gastrointestinal tract damage caused by repeated acute doses of alcohol in mice [77]. There are limited clinical data supporting the hypothesis that zinc supplementation is potentially therapeutic against some effects of alcoholic cirrhosis [76], but larger studies are needed to validate this point. The Role of Liver Transplantation There have been multiple recent studies and reviews concerning liver transplantation in patients with severe alcoholic cirrhosis [78–82]. There is a well-documented organ shortage for liver transplantation, and there are serious ethical issues concerning this controversial area that have precipitated these studies. Hepatitis C and ALD are the two major reasons for liver transplantation in the US. Data clearly demonstrate that patients transplanted for ALD do (short- and long-term) as well as patients transplanted for hepatitis C or other types of liver disease. However, AH clearly is not an indication for liver transplantation at the current time. Virtually all centers require that alcoholic patients undergo formal psychiatric evaluation and treatment prior to transplantation. Many centers impose a ‘6-month rule’ of abstinence before being considered for orthotopic liver transplantation, however most centers also show some ﬂexibility with this rule. It is unusual for ALD alone to be the cause of graft failure. The majority of patients with ALD are not listed for liver transplantation for multiple reasons including continued alcohol consumption, improvement in liver function with abstinence, lack of interest, etc. Patients with ALD appear to have a higher incidence of certain malignancies

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of the upper airway and upper digestive tract. Therefore, these patients should be screened for these processes prior to transplantation and monitored carefully after transplantation. Data suggest that, following transplantation, patients who had ALD and those who were transplanted for other reasons consume alcohol at relatively similar rates, although those who had ALD may consume greater amounts. The rate of alcohol use increases over time for all transplant recipients. Some centers use multi-stage screening processes with risk stratiﬁcation to select patients with low rates of recidivism. Clearly, more studies are required to reﬁne our predictive capabilities for both recidivism and noncompliance. Quality of life appears to improve after liver transplantation due to any etiology, although those with non-alcohol etiologies may improve more.

Conclusions

The optimal management of all patients with ALD begins with a dramatic reduction or elimination of alcohol intake, which often can be successfully accomplished using ‘brief interventions’ by a nurse, primary care physician, or gastroenterologist. Abstinence can have a profound impact on survival even in patients with decompensated cirrhosis. Other lifestyle modiﬁcations should be employed (e.g., weight loss, smoking cessation) where appropriate. Although palliative, successful treatment of decompensation has signiﬁcant short-term survival beneﬁts. Proper nutrition and nutrition support have consistently been shown to be important. Certain drugs (e.g., corticosteroids or PTX) may be effective in selected patients. While no FDA-approved therapies are available, many new agents, such as anti-TNF antibody, are under investigation. Lastly, there are a host of complimentary and alternative medicine approaches that may prove beneﬁcial in treating the underlying disease. Transplantation is life-saving in certain abstinent patients with end-stage liver disease.

Acknowledgment Research support from the National Institute of Alcohol Abuse and Alcoholism (NIAAA) is gratefully acknowledged.

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56 McClain CJ, Hill D, Kugelmas M, Marsano L: Nutrition and liver disease; in Rm B (ed): Present Knowledge in Nutrition. Washington, International Life Sciences Institute, 2001, pp 483–496. 57 Hill DB, Devalaraja R, Joshi-Barve S, Barve S, McClain CJ: Antioxidants attenuate nuclear factor-kappa B activation and tumor necrosis factor-alpha production in alcoholic hepatitis patient monocytes and rat Kupffer cells, in vitro. Clin Biochem 1999;32:563–570. 58 Lee KS, Buck M, Houglum K, Chojkier M: Activation of hepatic stellate cells by TGF alpha and collagen type I is mediated by oxidative stress through c-myb expression. J Clin Invest 1995;96:2461–2468. 59 de la Maza MP, Petermann M, Bunout D, Hirsch S: Effects of long-term vitamin E supplementation in alcoholic cirrhotics. J Am Coll Nutr 1995;14:192–196. 60 Mezey E, Potter JJ, Rennie-Tankersley L, Caballeria J, Pares A: A randomized placebo controlled trial of vitamin E for alcoholic hepatitis. J Hepatol 2004;40:40–46. 61 Bjelakovic G, Nikolova D, Simonetti RG, Gluud C: Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis. Lancet 2004; 364: 1219–1228. 62 Miller ER 3rd, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E: Metaanalysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med 2005;142:37–46. 63 Meister A: Glutathione metabolism and its selective modiﬁcation. J Biol Chem 1988; 263: 17205–17208. 64 Pena LR, Hill DB, McClain CJ: Treatment with glutathione precursor decreases cytokine activity. JPEN J Parenter Enteral Nutr 1999; 23:1–6. 65 Iimuro Y, Gallucci RM, Luster MI, Kono H, Thurman RG: Antibodies to tumor necrosis factor alfa attenuate hepatic necrosis and inﬂammation caused by chronic exposure to ethanol in the rat. Hepatology 1997; 26: 1530– 1537. 66 Hultberg B, Berglund M, Andersson A, Frank A: Elevated plasma homocysteine in alcoholics. Alcohol Clin Exp Res 1993;17:687–689. 67 Cravo ML, Camilo ME: Hyperhomocysteinemia in chronic alcoholism: relations to folic acid and vitamins B(6) and B(12) status. Nutrition 2000;16:296–302. 68 Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H, Prieto J, Lu SC, Caballeria J, Rodes J, Mato JM: Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol 2000;33:907–914.

69 Halsted CH, Villanueva JA, Devlin AM, Chandler CJ: Metabolic interactions of alcohol and folate. J Nutr 2002;132(suppl):2367S–2372S. 70 Ji C, Kaplowitz N: Betaine decreases hyperhomocysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 2003;124:1488–1499. 71 Song Z, Zhou Z, Uriarte S, Wang L, Kang J, Chen T, et al: S-Adenosylhomocysteine sensitizes to TNF-alpha hepatotoxicity in mice and liver cells: a possible etiological factor in alcoholic liver disease. Hepatology 2004;40: 989– 997. 72 Bode JC, Hanisch P, Henning H, Koenig W, Richter FW, Bode C: Hepatic zinc content in patients with various stages of alcoholic liver disease and in patients with chronic active and chronic persistent hepatitis. Hepatology 1988; 8:1605–1609. 73 McClain CJ, Antonow DR, Cohen DA, Shedlofsky SI: Zinc metabolism in alcoholic liver disease. Alcohol Clin Exp Res 1986; 10: 582– 589. 74 Dinsmore W, Callender ME, McMaster D, Todd SJ, Love AH: Zinc absorption in alcoholics using zinc-65. Digestion 1985; 32: 238– 242. 75 Valberg LS, Flanagan PR, Ghent CN, Chamberlain MJ: Zinc absorption and leukocyte zinc in alcoholic and nonalcoholic cirrhosis. Dig Dis Sci 1985;30:329–333. 76 Weismann K, Christensen E, Dreyer V: Zinc supplementation in alcoholic cirrhosis. A double-blind clinical trial. Acta Med Scand 1979; 205:361–366. 77 Lambert JC, Zhou Z, Wang L, Song Z, McClain CJ, Kang YJ: Preservation of intestinal structural integrity by zinc is independent of metallothionein in alcohol-intoxicated mice. Am J Pathol 2004;164:1959–1966. 78 Roberts MS, Angus DC, Bryce CL, Valenta Z, Weissfeld L: Survival after liver transplantation in the United States: a disease-speciﬁc analysis of the UNOS database. Liver Transpl 2004;10:886–897. 79 Farges O, Saliba F, Farhamant H, Samuel D, Bismuth A, Reynes M, et al: Incidence of rejection and infection after liver transplantation as a function of the primary disease: possible inﬂuence of alcohol and polyclonal immunoglobulin. Hepatology 1996;23:240–248. 80 Pageaux GP, Bismuth M, Perney P, Costes V, Jaber S, Possoz P, et al: Alcohol relapse after liver transplantation for alcoholic liver disease: does it matter? J Hepatol 2003;38:629–634. 81 Buis CI, Wiesner RH, Krom RA, Kremers WK, Wijdicks EF: Acute confusional state following liver transplantation for alcoholic liver disease. Neurology 2002;59:601–605. 82 Bellamy CO, DiMartini AM, Ruppert K, Jain A, Dodson F, Torbenson M, et al: Liver transplantation for alcoholic cirrhosis: long term follow-up and impact of disease recurrence. Transplantation 2001;72:619–626.

Bergheim /McClain /Arteel

Table 1. The prevalence of hepatitis C antibody in alcoholics according to the severity of liver disease (LD) Reference

Deﬁnition of alcohol consumption

HCV antibody test

Pares et al. [15]

>80 g/day, 5 years

ELISA I RIBA I

Befrits et al. [25]

>75 g/day

ELISA II RIBA II

14 14

Sweden

Brillanti et al. [39]

ELISA I RIBA I

37 31

Italy

Bode et al. [19]

ELISA I

24.7

Bruix et al. [36]

ELISA I

Zarski et al. [51]

>80 g/day, 10 years

Controls %

Alcoholics without LD %

2.2

Alcoholics with LD, %

Alcoholics with cirrhosis, %

20.0–41.4

42.6

7.3

ELISA II RIBA II

13.6

Alcoholics with HCC %

Country

Spain

38.5

Germany

38.7

76

Spain

20 20

37.5 37.5

France

Verbaan et al. [24]

ELISA II RIBA II

14.5

Sweden

Nalpas et al. [43]

ELISA RIBA II

58.3 35.5

France

Mendenhall et al. [14]

ELISA I

Caldwell et al. [17]

ELISA I

Coelho-Little et al. [31]

RIBA II

Mendenhall et al. [18]

ELISA I RIBA II

1.1

RIBA I

0

Shimizu et al. [21]

>80 g/day, 5 years

Sata et al. [30]

3.0

4.8 25 10

4.2

27.1

USA

29

USA

43

USA

14.2 18.4

USA

53.3

35.9

58.3

Japan

ELISA II

55.5

Japan

ELISA I ELISA II

56 80

Japan

Nishiguchi et al. [35]

ELISA RIBA II

53.7 45

61 60

Chang et al. [22]

ELISA

30.9

29.6

Ishii et al. [20]

>80 g/day

complicating factors include changes in the diagnosis of hepatitis C (e.g., ﬁrst-generation EIA vs. RIBA II or PCR), study design (e.g., cross-sectional, case-control, prospective cohort), population studied (alcohol treatment program, liver disease clinic, patients admitted to hospital, etc.), measuring alcohol intake, and determination of liver damage (e.g., clinical, liver biopsy, etc.). This review acknowledges such complicating factors and presents the current views of the effects of alcohol and hepatitis C on liver disease.

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2.3

Japan 44.4

Taiwan

Background

Recent or lifetime alcohol consumption is usually determined with questionnaires, although recognized problems with questionnaires include unreliable results since patients may offer false information due to social stigma, denial, or deﬁcient memory. However, questionnaires have proven satisfactory as they have retest reliability and are generally accurate when contrasted with information obtained from patients’ relatives, or during conﬁdential interviews [8].

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Table 2. The prevalence of HCV RNA in alcoholics with different disease severity

Reference

Deﬁnitions of alcohol consumption

Befrits et al. [25]

>75 g/day

Zarski et al. [51]

>80 g/day, 10 years

Controls

Alcoholics without LD %

Alcoholics with LD, %

4.5 29

Caldwell et al. [17]

17

Coelho-Little et al. [31]

6.6 >80 g/day

Sata et al. [30] Oshita et al. [26]

7.780.8

Nishiguchi et al. [35]

Sweden 15

12.5

France France

18

USA

40

USA

82

Japan

4.3–84 >60 g/day, 5 years

Alcoholics with HCC %

11.4

Nalpas et al. [43]

Ishii et al. [20]

Alcoholics with cirrhosis, %

100

8.580.5 46

Japan Japan Japan

Liver cell injury, and thus liver diseases, can be indicated by elevated serum alanine aminotransferase (ALT) levels, but that is not always reliable since ALT levels ﬂuctuate and are also normal in 30–50% of HCV-infected patients [7, 9, 10]. Polymerase chain reaction (PCR) is used to identify hepatitis C RNA in the serum as it is a marker of current hepatitis C infection. HCV RNA tests are best for detecting acute HCV [9, 11]. Early clinical studies employed ﬁrst-generation antibody tests to detect HCV, and over-estimation of data was a concern with those tests as a result of their probability for false-positives [8]. Later studies used second-generation antibody tests, often with recombinant immunoblot assay (RIBA) or PCR conﬁrmation. Third-generation enzyme-linked immunosorbent assay (ELISA) antibody tests are the currently most common diagnostic tests [11]. ELISA tests have a 98% sensitivity and speciﬁcity for detecting HCV [9]. Hepatitis C infections proceed to chronic infections in more than 50% of patients, and in 20–25% resolve spontaneously [9]. Alcohol abuse signiﬁcantly reduces the chance for HCV clearance [12]. Some CHC infections are labeled ‘mild’ since they are asymptomatic, with minimally elevated ALT levels and mild histological lesions [10]. Mild CHC has a slow ﬁbrosis rate and is not always treated right away. In an Italian study with 9,997 liver disease patients, 70% were HCV antibody-positive, and 56.3% had the infection without other confounding factors. Thus most HCV-infected patients have HCV alone. Approximately

23% of the 9,997 liver disease patients consumed large amounts of alcohol (140 g/day for males, and 130 g/day for females) with 9.4% having alcohol abuse as the sole cause of liver disease [13], which emphasizes that there are fewer heavy drinkers than there are patients infected with HCV.

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Prevalence of Hepatitis C in Alcoholics

Multiple cross-sectional studies have examined the prevalence of hepatitis C infection in alcoholics. These studies evaluated a variety of alcoholic populations, including patients attending alcohol treatment programs (without known liver disease), patients attending liver clinics (with presumed liver disease), and hospitalized patients with advanced liver disease. The studies are summarized in tables 1 and 2. Using ﬁrst-generation immunosorbent assays (EIA), antibodies to HCV have been reported in up to 50% of chronic alcoholics with liver disease [14–22]. However, when patients were retested with RIBA, the number of positive cases decreased signiﬁcantly [14]. European studies using second-generation EIA in combination with RIBA found HCV in approximately 14% of alcoholic patients [23–25]. The prevalence rate of HCV antibodies in alcoholics varies between countries. For example, the rate is approximately 10% in the US [14], 14% in northern Europe and France, [23–25] and 45–80% in Japan (table 1) [20, 26].

287

In the US, about 48% of the adult population drinks regularly [27]. Eight to 24% of individuals who drink alcohol and almost one third of alcoholics with liver disease are anti-HCV-positive [28, 29]. The prevalence of HCV in those who drink is 7- to 10-fold higher than it is in the general population [14, 15, 17, 30, 31]. Approximately 15–20% of chronic alcoholics develop cirrhosis over 20– 30 years, though most heavy drinkers (150 g/day) do not develop signiﬁcant liver disease [32, 33]. Abstinence reduces hepatitis C viral levels and reduces liver damage. Sata et al. [30] showed a 10-fold decrease in HCV RNA levels after abstinence in half of the patients. Cromie et al. [34] reported a decrease in hepatitis C viral load and improvement in disease activity after 4 months of abstinence. However, Ishii et al. [20] reported histological progression even after abstinence.

Hepatitis C Markers and Severity of ALD

The prevalence of HCV RNA is increased in alcoholic patients, especially alcoholics with liver disease (table 2) [16, 17, 23–26, 30]. Although the prevalence of HCV RNA in alcoholics varies from one study to another, it is higher in patients with severe alcoholic disease. The rate reported ranges from 4% to as high as 84% in Japanese alcoholics with liver disease [16, 17, 23–26, 30]. In most studies, the HCV antibody in alcoholics was found to be closely associated with the presence of serum HCV RNA. However, Nishiguchi et al. [35] found positive HCV RNA in alcoholic patients who had negative HCV antibody. The prevalence of HCV antibody is higher in alcoholic patients with advanced liver disease, with the highest prevalence in cirrhosis and hepatocellular carcinoma (table 1) [14, 15, 17, 18, 21–23, 25, 30, 36]. Coelho-Little et al. [31] assessed HCV antibody by RIBA II in 100 consecutive alcoholic patients. HCV antibody was positive in 10% of alcoholics without liver disease and in 43% of alcoholics with liver disease. Four other European studies also found a higher prevalence of HCV antibody in alcoholics with cirrhosis, the prevalence being between 20 and 43% [15, 19, 23, 36]. Nishiguchi et al. [35] found HCV RNA in 10% of patients with ﬁbrosteatosis, 15% of patients with alcoholic hepatitis, 68% of patients with chronic hepatitis and 65% of patients with alcoholic cirrhosis. The prevalence of hepatitis C infection is highest in alcoholic patients with hepatocellular carcinoma [21, 23, 30, 36]. Approximately 75% of Spanish alcoholics with hepatocellular carcinoma patients were positive for HCV antibody compared to 55% of patients with cirrho-

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sis and 7.3% of controls [36]. In Japan, 58% of alcoholic patients with hepatocellular carcinoma were HCV antibody-positive, with HCV RNA present in 100% of antibody-positive patients [21, 30].

Histopathology in Alcohol and Hepatitis C

It is suggested that, in people without hepatitis C, ALD may develop particularly in men and women drinking above 40 and 20 g/day, respectively [32]. In ALD patients with hepatitis C, over 80% show improving histological signs when they stop drinking [32]. Tamai et al. [37] found alcohol-related histological changes that were not as frequently seen with HCV infection, whose severity was directly related to alcohol intake. These histological features were present regardless of HCV infection. The study suggested there is alcohol-induced liver damage independent of damage caused by HCV. Conversely, the investigators found features of hepatitis C liver damage that were not inﬂuenced by alcohol consumption. Another histopathological study from Japan analyzed the livers of alcoholics with hepatitis C and compared them to ﬁndings from patients with either hepatitis C, B, or ALD [38]. The study found that most ALD patients with HCV had liver damage similar to those seen with CHC, and not ALD. Brillanti et al. [39] also assessed the serological and histological features in 41 consecutive alcoholic patients: 36% of patients had positive HCV antibody and 73% of these had chronic active hepatitis, a lesion not caused by heavy alcohol consumption. Consequently it is suggested that HCV is the primary factor affecting liver damage in patients who are both alcoholic and are infected with HCV [38], and it is as a result that more studies have focused on alcohol’s inﬂuence on HCV liver disease in particular [8]. Alcoholics with hepatitis C have higher serum ALT levels and greater inﬂammation on liver biopsy as compared with alcoholics without hepatitis C. Fong et al. [40] found signiﬁcantly increased serum ALT and a histological activity index in 33 alcoholics with hepatitis C as compared with 86 alcoholics without hepatitis C. Nishiguchi et al. [35] looked at the relationship between HCV antibody and different histological lesions in 80 alcoholic patients with liver disease. In this study, patients with HCV RNA had higher histological indices of disease activity and higher ALT levels compared to alcoholic patients with negative HCV RNA [35].

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Alcohol and the Risk of Acquiring Hepatitis C 4

Effect of Alcohol on the Natural History of CHC

Hepatitis C progression is determined using the level of necroinﬂammation grade (A) and ﬁbrosis stage (F) as seen in biopsy, and those scores are directly associated with the risk for clinical complications [10]. Multiple studies have evaluated the effect of alcohol consumption on various outcomes of CHC (e.g., cirrhosis, hepatocellular carcinoma or death). Several of these studies are large, prospective and/or longitudinal. However, most are retrospective, cross-sectional or case-control studies. The deﬁnition of signiﬁcant alcohol use varies between studies, ranging between 30 and 80 g/day. For the purposes of this review, the effect of alcohol on three outcomes of hepatitis C are presented: (1) liver ﬁbrosis progression rate; (2) development of cirrhosis, and (3) mortality.

Alcohol and Hepatitis C

0–49 g alcohol daily

Fibrosis stage

>50 g alcohol daily

1

0–30

31–40

41–50

51–60

>60

Age at biopsy (years) 4

Fibrosis stage

Hepatitis C is most common in people exposed to HCV-positive blood, such as through transfusions, transplants and contaminated needles [9, 29]. Blood transfusions were the most common form of transmission before 1992 when HCV blood-screening tests were not available, but thereafter most HCV transmissions have occurred through intravenous drug use [9]. It has been suggested that the high prevalence of HCV in alcoholics relates to a history of intravenous drug use, but this assumption remains unproven. One study looked at the seroprevalence of hepatitis B and C in a group of patients without known viral hepatitis risk factors, and found that HCV seropositivity was signiﬁcantly greater in alcoholics than in non-alcoholics (10 vs. 0%), while hepatitis B seropositivity was similar in the 2 groups [41]. In 1991, two studies stated that anti-HCV prevalence was similar in alcoholics with and without HCV risk factors including intravenous drug use and transfusions [28]. Such studies suggest that heavy alcohol consumption is itself a predisposing factor for HCV infection. More recent studies found a high prevalence of HCV in alcoholics with a history of blood transfusion, suggesting that acute hepatitis C may progress to CHC more commonly in alcoholics than in non-alcoholics [24, 42, 43]. A recent case-control study of risk factors for sporadic hepatitis C demonstrated that alcohol consumption of 160 g/day was itself an independent risk factor for hepatitis C compared to controls (odds ratio = 24.0) [44].

1 0–10

11–20

21–30

31–40

>40

Duration of infection (years)

Fig. 1. Association between stage of ﬁbrosis and age at biopsy or duration of infection by alcohol consumption. Reprinted from Poynard et al. [45] with permission from Elsevier.

Impact of Alcohol on Fibrosis Progression Liver ﬁbrosis rate is increased in hepatitis C patients who chronically consume alcohol. The landmark study by Poynard et al. [45] assessed the effect of alcohol consumption on liver ﬁbrosis progression in 2,235 patients with biopsy-proven CHC. By multivariate analysis, alcohol consumption of 150 g/day was an independent factor associated with increased ﬁbrosis progression. Patients who drank 150 g/day had a 34% increased rate of ﬁbrosis as compared with non-drinkers (ﬁg. 1) [45]. In a smaller cross-sectional study, Pessione et al. [46] evaluated alcohol consumption and liver ﬁbrosis in 233 patients with HCV infection and previous liver biopsy. By multivariate analysis, the liver ﬁbrosis was related to age of the patient and average daily alcohol consumption (ﬁg. 2) [46], a ﬁnding reiterated by recent studies [47–49].

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289

400 Mean SRAC (g/week)

350 300 250 200 150 100 50 0 0

1

2

3

4

Fibrosis score

Fig. 2. Mean SRAC during the period preceding the diagnosis of HCV infection (expressed in grams per week), and histological ﬁbrosis expressed with the Knodell index. Statistical signiﬁcance: p ! 0.02 (univariate analysis).

A retrospective study from Sweden evaluated the effect of moderate lifetime alcohol consumption (!40 g/ day) on ﬁbrosis progression. A group of 78 hepatitis C patients underwent two liver biopsies with a median of 6.3 years between them. Patients with progressive ﬁbrosis consumed a greater amount of alcohol (5.7 vs. 2.6 g/day) and had a higher drinking frequency (4.0 vs. 3.0 drinks/ week). This is the ﬁrst study to show that minimal amounts of alcohol consumption increase ﬁbrosis progression in HCV-infected patients [50]. These ﬁndings should be interpreted with caution given the relatively small size of the study, the retrospective design, and the small differences in alcohol consumption between patients with progressive and non-progressive ﬁbrosis (difference of 3 g alcohol [about 1/8 of a glass of wine] per day). Another retrospective study looked at ﬁbrosis rates in 180 predominantly mild hepatitis C patients, whose alcohol consumption was either none, moderate (0–50 g/ day) or high (150 g/day). The study showed that the ﬁbrosis rate increased with increasing alcohol intake [51]. All patients had at least two biopsies with an interval of about 3.7 years, and did not receive any HCV treatment before and between the procedures. The study found that heavy alcohol consumption strongly affected ﬁbrosis and that even low alcohol levels are a risk factor for disease progression. Rigamonti et al. [52] studied 3 groups: hepatitis C patients who were abstainers, moderate drinkers (!50 g/ day), heavy drinkers (150 g/day); heavy drinkers who were hepatitis C-negative with no evidence of liver dis-

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ease, and controls who drank sensibly according to the WHO guidelines. The researchers found that alcohol intake, even moderate, increased the degree of piecemeal necrosis and ﬁbrosis [52]. It is said that some alcohol consumptions may be healthy due to its positive cardiovascular and anti-inﬂammatory effects [28, 32, 53], but the acceptable minimal amount of alcohol has been difﬁcult to ﬁnd. It is unclear whether 10–20 g/day affects the natural disease progression of mild hepatitis C patients who are not on antiviral therapy [8, 11, 28], and some investigators suggest that mild CHC patients may be permitted to drink a minimal 10–20 g/day of alcohol [28]. One study in Ireland studied the effect of light drinking on women with HCV [54]. Sachithanadan et al. [54] had 8 women in the non-drinking group, 8 in the very light drinking group (!1 U/month or !8 g/month), and 12 in the light drinking group (2– 18 U/ week or 16–144 g/week). The abstinent and verylight drinking groups were similar upon preliminary analysis and thus were grouped together. On ﬁnal evaluation, there was a pattern of increased ﬁbrosis and inﬂammation with increased alcohol intake. The study is limited by its small sample size, but indicates that even light drinking can affect liver disease. Monto et al. [53] found a similar pattern of increasing ﬁbrosis with increasing alcohol consumption in their 800patient study. They obtained a detailed history of alcohol use from HCV-infected patients undergoing liver biopsy. For patients who consumed !50 g/day of alcohol, the pattern was insigniﬁcant, indicating that even with such a large sample size, the amount of ﬁbrosis induced by low alcohol amounts may be too subtle to notice. The investigators emphasized that their study did not establish a ‘safe’ level of alcohol intake. Hence whether there is a safe amount of alcohol remains controversial and most researchers suggest abstinence [33]. Hézode et al. [55], on the other hand, found that alcohol consumption of 31–50 g/day results in a signiﬁcant increase in ﬁbrosis. They made their ﬁnding upon observing ﬁbrosis and histological activity in 260 CHC patients who were consistently consuming no alcohol, 1–20, 21– 30 or 31–50 g/day (ﬁg. 3). The study also found a direct relationship between steatosis and histological lesions. A recent study demonstrated a synergistic interaction between steatosis and small alcohol consumption as a contributory factor in extensive liver ﬁbrosis. The median progression rate of ﬁbrosis was about twice as high among drinkers with steatosis than among drinkers without steatosis or nondrinkers [56]. Another study also evaluated HCV carriers and found a relationship between steatosis

Jamal/Saadi/Morgan

80

Fibrosis F0–F1

F2–F3–F4

71.0 70

67.6

65.6 61.8

Patients (%)

60 50 38.2

40

34.4

32.4

29.0

30 20

Fig. 3. Relationship between histological ﬁ-

brosis (METAVIR scoring system) and the level of alcohol intake in patients with chronic hepatitis C. Reprinted from Hézode et al. [55] with permission from Blackwell.

10 0 0

and alcohol intake, though not to histological activity [49]. Collier et al. [57] further found that in CHC patients, progressive ﬁbrosis could be predicted by age, steatosis and baseline ﬁbrosis, and that the latter two plus lobular inﬂammation could also indicate the patient’s ﬁbrosis rate. One study prospectively looked at 214 HCV carriers who underwent two biopsies and, in contrast to previous studies, found that the rate of ﬁbrosis was not associated with alcohol intake or steatosis but rather to age and ﬁbrosis at ﬁrst biopsy [58]. The study population had generally mild hepatitis C, however, and most patients had low alcohol intake (4.5–5 U/week or 36–40 g/day).

1–20

21–30

31–50

Alcohol intake (g/day)

Alcohol, Hepatitis C and the Development of Cirrhosis Chronic consumption of moderate-to-large amounts of alcohol enhances the development of cirrhosis in CHC patients. One study found patients with HCV alone had a relative risk of 9 for developing cirrhosis, compared to 15 for patients with alcohol abuse alone; the compounded risk was 147 for patients with both HCV and alcohol abuse [28]. One of the strongest studies showing the effect of chronic alcohol consumption on the development of cirrhosis in hepatitis C is the ‘Dionysus’ study [59]. This is a prospective, population-based study of 6,917 inhabitants of a town in northern Italy. At entry into the study clinical ﬁndings, blood tests (including HCV antibody) and lifetime alcohol consumption were recorded. Patients were evaluated every 6 months for 3 years. Clini-

cally suspected cirrhosis was conﬁrmed by liver biopsy. Sixty-two percent of patients drank alcohol of which 21% consumed 130 g/day. Patients who consumed 130 g/day were more likely to develop cirrhosis than were patients drinking !30 g/day (i.e., chronic alcohol intake was associated with development of cirrhosis). More importantly, 32% of HCV-positive patients drinking 130 g/day developed cirrhosis compared to 10% of patients with moderate alcohol consumption (!30 g/day). Thus, this large, prospective population-based study suggests the risk of developing cirrhosis is higher in hepatitis C patients who drink 13 drinks/day as compared with hepatitis C patients drinking !3 drinks/day. Several large cohort studies report an increased risk of cirrhosis in hepatitis C patients who drink moderate-tolarge amounts of alcohol. In a US community-based prospective cohort study, Thomas et al. [60] followed 1,667 HCV-infected injection drug users for an average of 8.8 years. End-stage liver disease was assessed every 6 months. In a multivariate model, the risk of end-stage liver disease was higher in persons older than 37 years of age and in persons ingesting 1260 g alcohol/week. As compared with non-drinkers, the relative incidence of end-stage liver disease was 3.6 for persons drinking 137 g/day and was 1.57 for those drinking 13–37 g/day. Harris et al. [61] assessed risks for cirrhosis in a case-control study of 836 patients transfused during the late 1960s and early 1970s. Compared with non-drinkers without hepatitis C, patients with hepatitis C had a 7.8-fold increased risk of cirrhosis. Patients with a history of heavy alcohol abuse had a 4-fold increased risk for cirrhosis, while patients with hepatitis

Alcohol and Hepatitis C

Dig Dis 2005;23:285–296

291

100 HCV

HCV-ETOH

90 80

Cirrhosis (%)

70

a a

60 50 40 30 20

Fig. 4. Histological results over four de-

10

cades of HCV exposure with or without alcohol. a Signiﬁcantly different by 2 test: p ! 0.01.

0

Total alcohol consumption (kg)

350

1st decade

a

300 b

250 200 150 100 50 0 Lifetime consumption

Consumption during HCV

Fig. 5. Comparison of total alcohol consumption between subjects

with cirrhosis and those with chronic hepatitis: calculated over the patient’s lifetime (left) and during the period of infection with HCV (right). a p = 0.018; b p = 0.02. ) = Chronic hepatitis; $ = cirrhosis.

C infection and a history of heavy alcohol abuse had a 31-fold increased risk for cirrhosis. Roudot-Thoraval et al. [62] conducted a multicenter study in France on 6,664 patients with HCV infection. At least one liver biopsy was performed in 5,789 cases. Cirrhosis was present in 21.4% of cases. Logistic regression analysis showed that cirrhosis was independently related to excessive alcohol intake, the route of infection, increasing age, and HBsAg positivity. In case-control studies of hepatitis C, heavy alcohol consumption is an independent risk for the progression to cirrhosis [63–66]. Corrao and Arico [63] compared 285 HCV-infected patients with 417 controls subjects without

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2nd decade

3rd decade

4th decade

any history of liver disease. Alcohol intake of 150 g/day was associated with an increased risk of cirrhosis in the HCV-positive and HCV-negative patients with relative risks of 26.1 and 4.4, respectively. The combination of alcohol and hepatitis C multiplied the risk of cirrhosis at a consumption level of 1125 g/day. In another retrospective study of 176 patients with biopsy-proven hepatitis C, Wiley et al. [67] demonstrated an increased risk of cirrhosis in alcohol-drinking patients, who constituted women drinking 140 g and men drinking 160 g/day. The rate at which subjects developed cirrhosis was faster in the alcohol group; 58% of the alcohol group was cirrhotic by the second decade of hepatitis C infection as compared to 12% of the non-alcohol group (ﬁg. 4) [67]. Ostapowicz et al. [68] evaluated 234 patients with CHC looking at alcohol’s role on disease progression. They concluded that age and total lifetime alcohol consumption were independently associated with cirrhosis. The odds ratio was 1.16/100.00 g consumed during life. The study also showed a trend for increased severity of ﬁbrosis with increasing total alcohol consumption (ﬁg. 5). Alcohol, Hepatitis C and Mortality Mortality associated with HCV and ALD results from the development of liver ﬁbrosis and the subsequent occurrence of cirrhosis [6, 69]. The ﬁrst report on the effect of alcohol on the progression of CHC was published by Seeff et al. [70], who showed that more than two thirds of deaths from end-stage liver disease in a cohort of posttransfusion hepatitis patients followed for 18 years occurred in persons with associated alcoholism.

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25

Responders Non-responders

a, c

Subjects (%)

20

Fig. 6. Percentage of chronic hepatitis patients responding to interferon as a function of ethanol use. a p ! 0.01 vs. responders; b p ! 0.01 vs. 41–80 and 180 g/day in responders; c p ! 0.01 vs. abstainers.

a, c a, c

b 15 10 b 5 0

Abstainers

<40 g/day

41–80 g/day

>80 g/day

Liver-speciﬁc mortality and, perhaps, overall mortality are increased in hepatitis C patients who drink moderate-to-large quantities of alcohol. In a prospective cohort study, Niederau et al. [71] followed 838 HCV patients for a mean period of 50 months. The survival rate was decreased in patients with cirrhosis, long duration of disease, intravenous drug use and heavy alcohol consumption. Patients who drank 180 g/day had a higher mortality, and increased liver disease complications with a risk ratio of 2.3 [71]. A study of transfusion-associated hepatitis C suggests alcohol use may increase mortality. Harris et al. [72] assessed factors associated with liver disease and mortality in 924 transfusion recipients infected with HCV and 475 transfusion recipients negative for HCV antibodies (controls). Although there was no difference in all cause mortality and alcohol use between the 2 groups, HCV-infected patients were at an increased risk of dying from liver disease, particularly if they consumed excess alcohol [72]. Alcohol consumption supersedes the effect of HCV infection in the survival rate of patients with alcoholic cirrhosis. Serra et al. [73] recently studied 213 patients with alcoholic cirrhosis, 72 of whom had HCV. Eighty-six patients chose to abstain from alcohol after their diagnosis. The investigators found that survival was not associated with HCV, but rather to patient age and alcohol intake after diagnosis. Patients hospitalized with liver disease due to both alcohol and hepatitis C do worse than patients hospitalized with liver disease due to either alcoholic or hepatitis C. The risk of death in patients hospitalized with liver disease from both risk factors is signiﬁcantly higher (odds ratio 1.4) than that of patients with HCV liver disease

Ongoing or recent alcohol consumption reduces the response to interferon treatment. Okazaki et al. [74] prospectively evaluated the response rate to interferon therapy in heavy drinkers, light drinkers and non-drinkers. The virologic response rate to interferon treatment in the 3 groups was 0, 43 and 53%, respectively. Accordingly, the serum HCV-RNA disappeared at a signiﬁcantly lower rate in the heavy drinkers than in the non-drinkers group (12.5 and 58.3%, respectively). There was also signiﬁcant histological improvement in the abstainers but none in either drinking group. As all signiﬁcant differences were only seen between drinkers and non-drinkers, the effect of light-to-moderate alcohol intake on HCV treatment remains unclear. Consequently, some professionals state that people with low alcohol intake can neither be excluded from therapy nor forced into a period of abstinence for treatment [29]. In a large multicenter study of 245 hepatitis C patients who were treated with interferon, 20% had a history of alcohol consumption of 180 g/day. The number of sustained virologic responders decreased as the alcohol intake increased (ﬁg. 6) [75]. A recent retrospective study of 150 patients treated with interferon evaluated the treatment response rate based on total lifetime alcohol intake [76]. The relapse rate after completion of interferon treatment in drinkers was twice as high as in non-

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without alcohol use [1]. Patients with both risk factors are also younger at the time of admission and death, in comparison to patients hospitalized for either alcohol or hepatitis C alone [1].

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drinkers. The overall response rate was reduced from 33% in non-drinkers to 9% in heavy drinkers. The reason for the decreased response to interferon treatment in patients with a history of alcohol use is uncertain. Suggested reasons for the decreased response to interferon include lipid peroxidation products, increased hepatic iron stores, deﬁcient immunity, higher pretreatment levels of HCV-RNA [28], and increased HCV quasi-species in alcoholics [26, 74, 77, 78]. Most studies illustrated signiﬁcantly higher HCV-RNA viral levels [11, 26] and impaired cellular immunity [26] in habitual compared to non-habitual drinkers. The new combination interferon and ribavirin, and pegylated interferon- treatments have been shown to be more successful than the former interferon monotherapy [11], but currently there is a lack of studies assessing efﬁcacy of the treatments on alcoholic HCV-infected patients.

Conclusion

Approximately 10–25% of alcoholics are infected with hepatitis C, a 7- to 10-fold increase compared with the general population. The prevalence of hepatitis C infec-

tion is higher in alcoholics with cirrhosis or hepatocellular carcinoma than it is in alcoholics without liver disease. Alcoholics with hepatitis C infection have higher serum ALT and more inﬂammation on liver biopsy than alcoholics without hepatitis C. Serum ALT and viral load decrease when alcoholics cease drinking. Up to 60% of patients with hepatitis C have a past history of signiﬁcant alcohol use. As compared with nondrinkers, HCV-infected patients who consume 15 alcoholic drinks/day have more rapid progression of ﬁbrosis. Patients with hepatitis C and a history of signiﬁcant alcohol use have an increased risk of cirrhosis and, possibly, death. Heavy alcohol use in the recent past decreases the response to interferon treatment. The detrimental effect of small amounts of alcohol (!3 drinks/day) in patients with hepatitis C is strongly supported by most studies. Existing studies share no consensus on an acceptable, minimal amount of alcohol intake, and the idea of any safe amount of alcohol itself is controversial. Abstinence continues to be the predominant recommendation for liver disease patients. More large population studies are needed to further evaluate the hepatotoxic effects of small amounts of alcohol on patients with hepatitis C.

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46 Pessione F, Degos F, Marcellin P, Duchatelle V, Njapoum C, Martinot-Peignoux M, Degott C, Valla D, Erlinger S, Rueff B: Effect of alcohol consumption on serum hepatitis C virus RNA and histological lesions in chronic hepatitis C. Hepatology 1998;27:1717–1722. 47 Serra MA, Rodriguez F, del Olmo A, Escudero A, Rodrigo JM: Inﬂuence of age and date of infection on distribution of hepatitis C virus genotypes and ﬁbrosis stage. J Viral Hepat 2003;10:183–188. 48 Martin-Carbonero L, Benhamou Y, Puoti M, Berenguer J, Mallolas J, Quereda C, Arizcorreta A, Gonzalez A, Rockstroh J, Asensi V, Miralles P, Laguno M, Moreno L, Giron JA, Vogel M, Garcia-Samaniego J, Nunez M, Romero M, Moreno S, de la Cruz JJ, Soriano V: Incidence and predictors of sever liver ﬁbrosis in human immunodeﬁciency virus-infected patients with chronic hepatitis C: a European collaborative study. Clin Infect Dis 2004;38:128–133. 49 Fabris P, Floreani A, Carlotto A, Giordani MT, Baldo V, Stecca C, Marchioro L, Tramarin A, Bertin T, Negro F, de Lalla F: Alcohol is an important co-factor for both steatosis and ﬁbrosis in northern Italian patients with chronic hepatitis C. J Hepatol 2004;41:644–651. 50 Westin J, Lagging LM, Spak F, Aires N, Svensson E, Lindh M, Dhillon AP, Norkrans G, Wejstal R: Moderate alcohol intake increases ﬁbrosis progression in untreated patients with hepatitis C virus infection. J Viral Hepat 2002; 9:235–241. 51 Zarski JP, Hutchison JM, Bronowicki JP, Sturm N, Garcia-Kennedy R, Hodaj E, Truta B, Wright T, Gish R: Rate of natural disease progression in patients with chronic hepatitis C. J Hepatol 2003;38:307–314. 52 Rigamonti C, Mottaran E, Reale E, Rolla R, Cipriani V, Capelli F, Boldorini R, Vidali M, Sartori M, Albano E: Moderate alcohol consumption increases oxidative stress in patients with chronic hepatitis C. Hepatology 2003;38: 42–49. 53 Monto A, Patel K, Bostrom A, Pianko S, Pockros P, McHutchison JG, Wright TL: Risks of a range of alcohol intake on hepatitis C-related ﬁbrosis. Hepatology 2004;39:826–834. 54 Sachithanadan S, Kay E, Leader M, Fielding JF: The effect of light drinking on HCV liver disease: the jury is still out. Biomed Pharmacother 1997;51:295–297. 55 Hézode C, Lonjon I, Roudot-Thoraval F, Pawlotsky JM, Zafrani ES, Dhumeaux D: Impact of moderate alcohol consumption on histological activity and ﬁbrosis in patients with chronic hepatitis C, and speciﬁc inﬂuence of steatosis: a prospective study. Aliment Pharmacol Ther 2003;17:1031–1037. 56 Serfaty L, Poujol-Robert A, Carbonell N, Chazouilleres O, Poupon RE, Poupon R: Effect of the interaction between steatosis and alcohol intake on liver ﬁbrosis progression in chronic hepatitis C. Am J Gastroenterol 2002; 97:1807–1812.

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64 Serfaty L, Chazouilleres O, Poujol-Robert A, Morand-Joubert L, Dubois C, Chretien Y, Poupon RE, Petit JC, Poupon R: Risk factors for cirrhosis in patients with chronic hepatitis C virus infection: results of a case-control study. Hepatology 1997;26:776–779. 65 Pol S, Lamorthe B, Thi NT, Thiers V, Carnot F, Zylberberg H, Berthelot P, Brechot C, Nalpas B: Retrospective analysis of the impact of HIV infection and alcohol use on chronic hepatitis C in a large cohort of drug users. J Hepatol 1998;28:945–950. 66 Khan KN, Yatsuhashi H: Effect of alcohol consumption on the progression of hepatitis C virus infection and risk of hepatocellular carcinoma in Japanese patients. Alcohol Alcohol 2000;35:286–295. 67 Wiley TE, McCarthy M, Breidi L, McCarthy M, Layden TJ: Impact of alcohol on the histological and clinical progression of hepatitis C infection. Hepatology 1998;28:805–809. 68 Ostapowicz G, Watson KJ, Locarnini SA, Desmond PV: Role of alcohol in the progression of liver disease caused by hepatitis C virus infection. Hepatology 1998;27:1730–1735. 69 Dufour MC, Stinson FS, Caces MF: Trends in cirrhosis morbidity and mortality: United States, 1979–1988. Semin Liver Dis 1993;13: 109–125. 70 Seeff LB, Bales ZB, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger B, Gitnick G, Knodell RG, Perrillo RP, Stevens CE, Hollingsworth CG: Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med 1992; 327: 1906– 1911. 71 Niederau C, Lange S, Heintges T, Erhardt A, Buschkamp M, Hurter D, Nawrocki M, Kruska L, Hensel F, Petry W, Haussinger D: Prognosis of chronic hepatitis C: results of a large, prospective cohort study. Hepatology 1998;28: 1687–1695.

72 Harris HE, Ramsay ME, Andrews N, Eldridge KP: Clinical course of hepatitis C virus during the ﬁrst decade of infection: cohort study. BMJ 2002;324:450–453. 73 Serra MA, Escudero A, Rodriguez F, del Olmo JA, Rodrigo JM: Effect of hepatitis C virus infection and abstinence from alcohol on survival in patients with alcoholic cirrhosis. J Clin Gastroenterol 2003;36:170–174. 74 Okazaki T, Yoshihara H, Suzuki K, Yamada Y, Tsujimura T, Kawano K, Yamada Y, Abe H: Efﬁcacy of interferon therapy in patients with chronic hepatitis C. Comparison between non-drinkers and drinkers. Scand J Gastroenterol 1994;29:1039–1043. 75 Loguercio C, Di Pierro M, Di Marino MP, Federico A, Disalvo D, Crafa E, Tuccillo C, Baldi F, del Vecchio Blanco C: Drinking habits of subjects with hepatitis C virus-related chronic liver disease: prevalence and effect on clinical, virological and pathological aspects. Alcohol Alcohol 2000;35:296–301. 76 Tabone M, Sidoli L, Laudi C, Pellegrino S, Rocca G, Della Monica P, Fracchia M, Galatola G, Molinaro GC, Arico S, Pera A: Alcohol abstinence does not offset the strong negative effect of lifetime alcohol consumption on the outcome of interferon therapy. J Viral Hepat 2002;9:288–294. 77 Mochida S, Ohnishi K, Matsuo S, Kakihara K, Fujiwara K: Effect of alcohol intake on the efﬁcacy of interferon therapy in patients with chronic hepatitis C as evaluated by multivariate logistic regression analysis. Alcohol Clin Exp Res 1996;20(suppl):371A–377A. 78 Ohnishi K, Matsuo S, Matsutani K, Itahashi M, Kakihara K, Suzuki K, Ito S, Fujiwara K: Interferon therapy for chronic hepatitis C in habitual drinkers: comparison with chronic hepatitis C in infrequent drinkers. Am J Gastroenterol 1996;91:1374–1379.

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Alcohol and Gastrointestinal Cancer

Epidemiology Chronic alcohol consumption is a strong risk factor for cancer development in the upper alimentary tract (UADT) and plays a critical role in hepatocarcinogenesis [1, 2]. Additionally, alcohol consumption increases the risk for colorectal and breast cancer [1, 2]. Epidemiological studies have demonstrated a correlation between alcohol ingestion and the development of cancer in these organs and clearly show ethanol as crucial compound, acting by various pathophysiological mechanisms [1, 2]. Animal Experiments The results of animal experiments on alcohol and the development of gastrointestinal cancer depend on the setting, the type of carcinogen used, route, time, duration, and dosage of carcinogen and alcohol administration. Chronic alcohol administration without the application of a carcinogen or a procarcinogen does not increase cancer risk. Local application of alcohol to oral or esophageal mucosa is supposed to increase cancer risk due to an irritant effect [1], whereas the majority of studies with systemic application of ethanol show a stimulative effect on chemically induced carcinogenesis with enhancement of tumor initiation and promotion [2]. In rodents chronic life-long exposure to alcohol did not increase cancer risk, thus proving that metabolites but not alcohol itself exert carcinogenic effects [3]. Experimental settings dealing with the two known procarcinogens, dimethylhydrazine (DMH) and azoxymethane (AOM), to study the effects on colorectal mucosa showed different results depending on the study conditions [4, 5]. As a striking result it could be proven that both agents’ carcinogenic effects relied on the metabolic activation by CYP2E1-dependent microsomal enzymes. The conclusions derived from these animal experiments are the following [6, 7]. Alcohol rather than other beverage constituents inﬂuences colonic carcinogenesis. Carcinogenesis in the right and left colorectum is affected differently by alcohol and may depend on the levels of alcohol consumption. Thus high alcohol intake (18–33% of total calories) inhibits carcinogenesis in the right colon and exerts no effects on the left colon, while lower alcohol consumption (9–12% of total calories) enhances carcinogenesis in the left but not the right colon. Ethanol was shown to inﬂuence carcinogenesis during the preinduction and/or induction but not in the promotion phase. Tumor incidence may be inﬂuenced by an interaction of ethanol and procarcinogen me-

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tabolism. It must be emphasized that, in one experiment with DMH, ethanol ingestion enhanced tumor development only in the rectum, but not in the colon [4]. In this study ethanol was administered during acclimatization and initiation, but at the time of procarcinogen application ethanol already disappeared. A similar study did not conﬁrm these results [5]. In addition, in two other studies the induction of rectal cancer using the primary carcinogen acetoxymethylmethyl nitrosamine (AMMN) resulted in an acceleration of carcinogenesis [8]. AMMN was applied locally to the rectal mucosa of rats and the animals were endoscoped regularly. Since chronic ethanol administration, either as liquid diets or intragastrically, accelerates the appearance of rectal cancer induced by AMMN, it seems most likely that alcohol enhances carcinogenesis at least in part by local mechanisms in the rectal mucosa and not only by increasing the activation of procarcinogens. Furthermore, in these studies AA concentrations were experimentally increased by the administration of cyanamide, an AA-dehydrogenase (ALDH) inhibitor, resulting in a stimulation of colorectal carcinogenesis induced by AMMN and emphasizing the pathogenic role of AA [8].

Possible Pathophysiological Mechanisms of Alcohol-Associated Carcinogenesis

Local Effects Alcohol acts as a solvent that enhances the penetration of carcinogenic compounds into the mucosa and may also facilitate the uptake of environmental (pro)-carcinogens such as tobacco smoke after alteration of cell surfaces due to direct cytotoxic effects. Concerning the development of cancer of the upper gastrointestinal tract, the atrophy and lipomatous metamorphosis of the parotid and submaxillary gland due to chronic alcohol consumption with subsequent functional impairment also contribute to local damage and carcinogenesis. Insufﬁcient rinsing of the mucosa leads to higher concentrations of locally acting carcinogens in addition to a prolonged contact time [9]. Other local effects besides direct toxicity of alcohol include altered gastrointestinal motility, enhanced gastroesophageal reﬂux with developing esophagitis and metaplasia, and exposure to carcinogenic agents other than AA at least in traces, e.g. polycyclic hydrocarbons, asbestos ﬁber and nitrosamines [2, 10, 11].

Seitz /Maurer /Stickel

Acetaldehyde Recent research has identiﬁed AA rather than alcohol itself as a highly toxic, mutagenic and carcinogenic agent [12], interfering at many sites with DNA synthesis and repair and therefore carcinogenesis [13]. According to the International Agency for Research on Cancer there is sufﬁcient evidence to identify AA as a carcinogen in animals [13]. In the gastrointestinal tract AA as the primary metabolite of ethanol is generated by mucosal and/or bacterial alcohol dehydrogenases (ADHs) [14]. Numerous in vitro and in vivo experiments in prokaryocytic and eukaryocytic cell cultures and in animal models have proven the mutagenic and carcinogenic effects of AA, causing point mutations in the hypoxanthine-guanine-phosphoribosyl transferase locus in human lymphocytes, inducing sister chromatid exchanges, and gross chromosomal aberrations [15–17]. AA induces inﬂammation and metaplasia of the tracheal epithelium, delays cell cycle progression, stimulates apoptosis, and enhances cell injury associated with hyperregeneration [12, 18]. The impairment of DNA repair by AA is in part due to the direct inhibition of O6-methylguanyltransferase, an enzyme important for the repair of adducts caused by alkylating agents [19]. The covalent binding to DNA and the formation of stable adducts represent possible mechanisms by which AA could trigger the occurrence of replication errors and/ or mutations in oncogenes or tumor-suppressor genes [20], and has been shown in different organs of alcoholfed rodents or in the leukocytes of alcoholics [21]. In addition, AA adducts represent neoantigens triggering cytotoxic immune responses at least in part because of the production of speciﬁc antibodies. The effects due to the interference of AA with folate metabolism leading to DNA hypomethylation will be discussed below. Recent and striking evidence for the causal role of AA in alcohol-associated carcinogenesis derives from genetic linkage studies in alcoholics. Individuals accumulating AA due to polymorphism and/or mutation in genes coding for alcohol-metabolizing enzymes have been shown to have an increased cancer risk [22]. Polymorphisms of ADH 1B (ADH1B) and ADH 1C (ADH1C) may modulate AA levels. While the ADH1B*2 allele encodes for an enzyme that is approximately 40 times more active than the enzyme coded by the ADH1B*1 allele, the ADH1C*1 transcription product is 2.5 times more active than that of ADH1C*2. While the ADH1B*2 allele is rare in the Caucasian population and seems to exert a protective effect against (chronic) alcohol consumption in Asia because of the toxic side effects related to high AA levels [12, 23], studies on ADH1C polymorphism in Caucasians

have shown contradictory results. Whereas some studies conﬁrmed an increased risk of oropharyngeal and laryngeal cancer in individuals with the ADH1C*1 allele [24, 25], other case-control studies have not been able to prove this association [26–30]. However, the contradictory results may be due to different and insufﬁcient study designs, i.e. extremely low alcohol intake, mixed ethnicity, and geographical differences. A study on the frequency of ADH1C polymorphism in alcoholic patients with upper gastrointestinal tract cancer in comparison to agematched alcoholics without cancer showed a signiﬁcantly increased cancer risk in individuals with the ADH1C*1 allele, associated with elevated AA levels in the saliva of individuals homozygous for ADH1C*1 [31]. Increased salivary AA levels in these individuals as well as in individuals with ineffective aldehyde dehydrogenase activity with resulting local toxicity [32] may explain their increased cancer risk. These observations have been conﬁrmed by the results of animal experiments. AA-fed rats showed a severe hyperregeneration of the upper gastrointestinal mucosa [33] – very similar to the morphological changes after chronic alcohol consumption [9, 34]. After sialoadenectomy hyperregeneration did not occur, supporting the hypothesis of the carcinogenic effects of salivary AA. AA can also be produced by gastrointestinal bacteria [35–37]. The amount of AA per gram of tissue was found to be highest in the colonic mucosa compared to all other tissues, primarily due to the production by fecal bacteria, as animal studies with germ-free rats have shown [8]. The toxic mucosal effects of AA result in decreasing cell numbers in the functional compartment of the colonic crypt, being answered secondarily by compensatory hyperregeneration with increased crypt cell production rates and an extension of the proliferative compartment towards the lumen of the crypt [18, 38]. This observation was paralleled by a signiﬁcant increase in rectal mucosal ornithine decarboxylase activity [8]. This alteration of crypt cell dynamics favors the development of colorectal cancer [39]. As the alcohol-associated hyperregeneration of the colonic mucosa is especially pronounced with increasing age, chronic alcohol consumption during life time may additionally result in an elevated risk of developing colorectal cancer. In contrast, cell differentiation with regard to the cytokeratin expression pattern was not inﬂuenced by chronic alcohol consumption as well as regulatory factors involved in carcinogenesis and/or apoptosis [40]. Although AA production by fecal bacteria obviously dominates in the colon, recent studies observed that individuals with ADH1C*1 allele

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homozygosity also have an increased risk of colorectal cancer due to their elevated AA levels as already discussed above. Thus there is some evidence for the involvement of AA in alcohol-associated carcinogenesis: • High AA levels occur in the saliva and in the colon following alcohol consumption. • Oral bacteria are capable of oxidizing AA from ethanol, and salivary AA levels are elevated in patients with upper gastrointestinal tract cancer as well as in individuals with a poor dental state and cigarette smokers, both conditions also favoring cancer risk [41]. • AA leads to mucosal hyperregeneration, and the colonic crypt cell production rate signiﬁcantly correlates with AA levels in the colonic mucosa. • Animal experiments have shown an increased occurrence of colorectal tumors induced by the speciﬁc locally acting carcinogen AMMN, when cyanamide, an ALDH inhibitor, was applied and AA levels were increased. • Colonic AA levels show a signiﬁcant inverse correlation with mucosal folate concentrations supporting in vitro data showing a destruction of folate by AA. • Individuals with the inactive form of ALDH2 resulting in elevated AA concentrations exhibit an increased risk for UADT and colorectal cancer due to chronic alcohol consumption. • In individuals homozygous for the ADH1C*1 allele, salivary AA levels are elevated thus increasing the risk of developing UADT cancer. Induction of Cytochrome P4502E1 Chronic ethanol consumption, even if moderate [42], leads to an induction of CYP2E1 in the liver and other organs including the mucosa of the gastrointestinal tract of rodents [43] and men [44]. Aside from metabolizing ethanol to AA, CYP2E1 is also involved in the metabolism of various xenobiotics, including activation of procarcinogens (nitrosamines, aﬂatoxin, vinylchloride, polycyclic hydrocarbons, hydrazines) to carcinogens [2]. Induction of CYP2E1 in the UADT may be particularly relevant with respect to procarcinogens present in tobacco smoke and the well-known synergistic effect of drinking and smoking on UADT carcinogenesis. Thus, the microsomal activation of nitrosopyrrolidine, present in tobacco smoke, to its ultimate carcinogen is signiﬁcantly enhanced in the esophagus after alcohol ingestion in rats [45]. The effect of chronic ethanol on the induction of CYP2E1 and the activation of a procarcinogen has been

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proven in various animal experiments using AOM as an inducing procarcinogen for colorectal cancer. AOM metabolism was found to be inhibited in the presence of ethanol, but signiﬁcantly increased when ethanol was withdrawn after chronic consumption, a condition where CYP2E1 is induced and therefore available for the activation of AOM [46]. As a result of the induction of colorectal CYP2E1 there may be an increased activation of dietary nitrosamines and polycyclic hydrocarbons in feces as a possible mechanism of alcohol-related colorectal carcinogenesis. The interaction between ethanol and procarcinogen metabolism is complex and may depend, among others, on the degree of CYP2E1 induction, on the chemical structure of the procarcinogen, and the presence or absence of ethanol in the body during procarcinogen metabolism [2]. In addition, induction of CYP2E1 leads to generation of ROS. ROS generation may contribute to the development of UADT cancer as was demonstrated in an animal experiment. Chronic ethanol consumption increased the carcinogenesis induced by N-nitrosomethylbenzylamine in the esophagus in associated with an increasing production of ROS, whereas administration of the scavenger tocopherol inhibited this effect [47]. Interestingly, colorectal hyperregeneration, observed after chronic alcohol administration to rats most likely due to AA, was also attenuated by the concomitant administration of vitamin E [48]. Nutritional Factors In heavy drinkers, the entire nutritional status is impaired due to primary and secondary malnutrition. Occurring deﬁciencies of vitamins and trace elements may contribute to alcohol-associated carcinogenesis [2]. The increased oxidative stress following ethanol metabolism enhances the requirement for glutathione and -tocopherol as well as the need for methyl groups, since the dietary lack of methyl may support (hepatic) carcinogenesis [49]. Folate deﬁciency due to low intake and destruction by AA is common in chronic alcohol consumers and contributes to an inhibition of transmethylation as an important factor in the regulation of genes involved in carcinogenesis [50]. In the colon of chronically ethanol-fed rats a significant reduction in folate has been reported in association with increased AA levels [36]. This observation may at least in part explain the genomic DNA hypomethylation in the colonic mucosa following chronic alcohol consumption [51]. However, no effect of alcohol consumption was found when the region of the p53 gene was examined. According to epidemiological data in individuals

Seitz /Maurer /Stickel

with low folate and methionine intake and an alcohol consumption of 120 g/day, the risk of distal colorectal cancer is increased more than 7-fold [50]. The role of nutritional deﬁciency in alcohol-associated gastrointestinal tract cancer remains uncertain. The lack of iron, as occurs in the Plummer-Vinson syndrome, has been considered as a possible mechanism in UADT carcinogenesis. On the other hand, regular consumption of fruit and green vegetables may reduce the risk from exposure to many carcinogenic agents. The lack of zinc and selenium may also support carcinogenesis. Besides the impact of zinc on nitrosamine activation by CYP2E1 [52], zinc deﬁciency may also disturb vitamin A metabolism because of its important role in the conversion of retinol (ROL) to retinal, as well as in the synthesis and secretion of ROL-binding protein in the liver. The lack of zinc also reduces glutathione transferase, an enzyme important in the detoxiﬁcation of carcinogens in vivo. Furthermore, zinc depletion is associated with increased cell proliferation in the esophageal mucosa [53]. Changes in ROL metabolism due to alcohol may have a pathophysiological impact on alcohol-associated carcinogenesis as retinoic acid (RA), the most active form of vitamin A, is an important regulator of normal epithelial cell growth, function and differentiation. Under normal conditions ingested ROL is metabolized to retinaldehyde via cytosolic ADH, microsomal dehydrogenases, and several types of cytosolic ROL dehydrogenase, and retinaldehyde is further oxidized to RA via ALDH. RA binds to RA receptors, initiating intracellular signal transduction leading to a cascade of events and ﬁnally to a decrease in cell regeneration. The interaction between ethanol and retinoid metabolism is quite complex as the two substrates share common pathways: ADH, ALDH and CYP2E1. Decreasing RA leads to a functional downregulation of RA receptors and to a 10-fold increased expression of the AP1 gene and thus to an increase in c-jun and c-fos and to hepatocellular hyperproliferation that can be experimentally reversed by RA supplementation [54, 55]. These data emphasize the importance of low RA levels due to chronic alcohol consumption in hepatocarcinogenesis. In contrast, ROL concentrations in extrahepatic tissues such as the gastrointestinal mucosa were found to be rather increased than decreased following chronic alcohol consumption [56]. This observation was also conﬁrmed in alcoholics with oropharyngeal cancer, in whom normal ROL concentrations were found in normal oral mucosa adjacent to cancerous tissue [57]. One underlying mechanism may be the increased mobilization of retinyl esters from the liver to extrahepatic tissues such as the gastro-

intestinal mucosa [58] as well as an inhibition of ROL oxidation in the intestine [59]. This may be the result of a competitive inhibition of the metabolism of ROL to RA at the binding site of ADH (ADH class I and IV) in the presence of ethanol, especially relevant in the colon, explaining the accumulation of ROL in the colonic mucosa with the following reduction in RA. Oxidation of ROL to RA is probably the rate-limiting step in the generation of RA, and an inhibition of RA generation by AA has been reported in the esophageal mucosa [60]. In addition, it is most likely that enhanced RA degradation also occurs through induction of CYP2E1 in the colonic mucosa. It is quite noteworthy that class IV ADH – in contrast to class I – is not expressed in the human colorectal mucosa. However, it could be shown that in a number of biopsies from colorectal polyps in patients with chronic alcohol consumption, class IV was expressed [60]. One explanation for such a de novo expression of class IV ADH could be RA deﬁciency in a critical premalignant condition to guarantee increased generation of RA to suppress mucosal hyperregeneration. Thus, as a consequence of chronic ethanol ingestion, the mucosal hyperregeneration may not only be due to the direct toxic effect of AA, but also to RA deﬁciency, and AA may contribute by preventing its generation. Epidemiological studies have shown that the supplementation of -carotene, a precursor of ROL, in smokers does not prevent the development of lung cancer, but in contrast supported carcinogenesis, probably due to the concomitant consumption of alcohol [61]. Underlying effects may include low RA levels and the generation of toxic metabolites from RA via CYP2E1 metabolism [62].

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Conclusion

AA has proved to be a strong risk factor in upper gastrointestinal cancer and to be a weaker risk factor in colorectal cancer. According to more recent data, even at moderate doses (10–40 g/day) ethanol should be considered a risk factor in the development of gastrointestinal cancer, especially in patients with other associated risk factors. AA has been identiﬁed as the predominant pathophysiological agent in alcohol-associated carcinogenesis because of its mutagenic and carcinogenic properties, its binding to DNA and cellular proteins, its interference with folate and ROL metabolism, thus leading to secondary hyperregeneration, sometimes increased by local factors. AA is mainly produced by mucosal and bacterial

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ADH. ADH and ALDH polymorphisms modulate the individual risk of (gastrointestinal) carcinogenesis. Induction of CYP2E1 in mucosal cells in chronic alcohol consumers results in an increased generation of ROS and

in an increased activation of various dietary and environmental carcinogens. Nutritional deﬁciencies of zinc, selenium, folate, riboﬂavin, vitamin B6 and possibly RA may further affect alcohol-associated carcinogenesis.

References 1 Seitz HK, Stickel F, Homann N: Pathogenetic mechanisms of upper aerodigestive tract cancer in alcoholics. Int J Cancer 2004; 108: 483– 487. 2 Pöschl G, Seitz HK: Alcohol and cancer. Alcohol Alcohol 2004;39:1–11. 3 Ketcham AS, Wexler H, Mantel N: Affects of alcohol in mouse neoplasia. Cancer Res 1963; 23:703–709. 4 Seitz HK, Czygan P, Waldherr R, et al: Enhancement of 1,2-dimethylhydrazine induced rectal carcinogenesis following chronic ethanol consumption in the rat. Gastroenterology 1984;86:886–891. 5 McGarrity TJ, Via EA, Colony PC: Changes in the tissue sialic acid content and staining in dimethylhydrazine (DMH)-induced colorectal cancer: effects of ethanol. Gastroenterology 1986;90:A1543. 6 Hamilton SR, Sohn OS, Fiala ES: Effects of timing and quantity of chronic dietary ethanol consumption on azoxymethane induced colonic carcinogenesis and azoxymethane metabolism in Fischer 334 rats. Cancer Res 1987;47: 4305–4311. 7 Hamilton SR, Hyland J, McAvinchey D, et al: Effects of chronic dietary beer and ethanol consumption on experimental colonic carcinogenesis by azoxymethane in rats. Cancer Res 1987; 47:1551–1559. 8 Seitz HK, Simanowski UA, Garzon FZ, Rideout JM, Peters TJ, Koch A, Berger MR, Einecke H, Maiwald M: Possible role of acetaldehyde in ethanol related rectal carcinogenesis in the rat. Gastroenterology 1990;98:1–8. 9 Maier H, Born IA, Veith S, Adler D, Seitz HK: The effect of chronic ethanol consumption on salivary gland morphology and function in the rat. Alcohol Clin Exp Res 1986;10:425–427. 10 Alcohol drinking. IARC Working Group, Lyon, 13–20 October 1987. IARC Monogr Eval Carcinog Risks Hum 1988;44:35–45. 11 Obe G, Anderson D: International Commission for Protection against Environmental Mutagens and Carcinogens. ICPEMC Working Paper No. 15/1. Genetic effects of ethanol. Mutat Res 1987;186:177–200. 12 Seitz HK, Matsuzaki S, Yokoyama A, Homann N, Vakevainen S, Wang XD: Alcohol and cancer. Alcohol Clin Exp Res 2001;25:137–143. 13 Acetaldehyde. IARC Monogr Eval Carcinog Risk Chem Hum 1985;36:101–132. 14 Seitz HK, Oneta CM: Gastrointestinal alcohol dehydrogenases. Nutr Rev 1998;56:52–60. 15 Dellarco VL: A mutagenecity assessment of acetaldehyde. Mutat Res 1988;195:1–20.

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16 Helander A, Lindahl-Kiessling K: Increased frequency of acetaldehyde-induced sister-chromatid exchanges in human lymphocytes treated with an aldehyde dehydrogenase inhibitor. Mutat Res 1991;264:103–107. 17 Obe G, Jonas R, Schmidt S: Metabolism of ethanol in vitro produces a compound which induces sister-chromatid exchanges in human peripheral lymphocytes in vitro: acetaldehyde not ethanol is mutagenic. Mutat Res 1986;174: 47–51. 18 Simanowski UA, Suter P, Russel RM, Heller M, Waldherr R, Ward R, Peters TJ, Smith D, Seitz HK: Enhancement of ethanol induced rectal mucosal hyperregeneration with age in F244 rats. Gut 1994;35:1202–1106. 19 Espina N, Lima V, Lieber CS, Garro AJ: In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase. Carcinogenesis 1988;9:761–766. 20 Frank A, Seitz HK, Bartsch H, Frank N, Nair J: Immunohistochemical detection of 1,N6ethenodeoxyadenosine in nuclei of human liver by diseases predisposing to hepatocarcinogenesis. Carcinogenesis 2004;25:1027–1031. 21 Fang JL, Vaca CE: Detection of DNA adducts of acetaldehyde in peripheral white blood cells of alcohol abusers. Carcinogenesis 1997; 18: 627–632. 22 Yokoyama A, Muramatsu T, Ohmori T, Yokoyama T, Okuyama K, Takahashi H, Hasegawa Y, Higuchi S, Maruyama K, Shirakura K, Ishii H: Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics. Carcinogenesis 1998;19:1383–1387. 23 Borras E, Coutelle C, Rosell A, FernandezMuixi F, Broch M, Crosas B, Hjelmqvist L, Lorenzo A, Gutierrez C, Santos M, Szczepanek M, Heilig M, Quattrocchi P, Farres J, Vidal F, Richart C, Mach T, Bogdal J, Jornvall H, Seitz HK, Couzigou P, Pares X: Genetic polymorphism of alcohol dehydrogenase in Europeans: the ADH1B*2 allele decreases the risk for alcoholism and is associated with ADH1C*1. Hepatology 2000;31:984–989. 24 Harty LC, Caporaso NE, Hayes RB, Winn DM, Bravo-Otero E, Blot WJ, Kleinman DV, Brown LM, Armenian HK, Fraumeni JF, Shields PG: Alcohol dehydrogenase 3 genotype and risk of oral cavity and pharyngeal cancers. J Natl Cancer Inst 1997;89:1698–1705. 25 Coutelle C, Fleury B, Quattrocchi P, Chambrin H, Iron A, Couzigou P, Cassaigne A: Laryngeal and oropharyngeal cancer, and alcohol dehydrogenase 3 and glutathione S-transferase M1 polymorphism. Hum Genet 1997;99:319– 325.

26 Olshan AF, Weissler MC, Watson MA, Bell DA: Risk of head and neck cancer and the alcohol dehydrogenase 3 genotype. Carcinogenesis 2001;22:57–61. 27 Sturgis EM, Dahlstrom KR, Guan Y, Eicher SA, Strom SS, Spitz MR, Wei Q: Alcohol dehydrogenase genotype is not associated with risk of squamous cell carcinoma of the oral cavity and pharynx. Cancer Epidemiol Biomarkers Prev 2001;10:273–275. 28 Schwartz SM, Doody DR, Fitzgibbons ED, Rick S, Porter PL, Chen C: Oral squamous cell cancer risk in relation to alcohol consumption and alcohol dehydrogenase-3 genotypes. Cancer Epidemiol Biomarkers Prev 2001; 10: 1137–1144. 29 Brennan P, Lewis S, Hashibe M, Bell DA, Boffetta P, Bouchardy C, et al: Pooled analysis of alcohol dehydrogenase genotypes and head and neck cancer. A HuGE review. Am J Epidemiol 2004;15:1–16. 30 Zavras AI, Wu T, Laskaris G, Wang YF, Cartsos V, Segas J, et al: Interaction between a single nucleotide polymorphism in the alcohol dehydrogenase 3 gene, alcohol consumption and oral cancer risk. Int J Cancer 2002; 97: 526– 530. 31 Visapää JP, Götte K, Benesova M, Li JJ, Homann N, Conradt C, Inoue H, Tisch M, Hörmann K, Väkeväinen S, Salaspuro M, Seitz HK: Increased cancer risk in heavy drinkers with the alcohol dehydrogenase 3*1-allele possibly due to salivary acetaldehyde. Gut 2004; 53:871–876. 32 Väkeväinen S, Tillonen J, Agarwal D, Srivastava N, Salaspuro M: High salivary acetaldehyde after a moderate dose of alcohol in ALDH2-deﬁcient subjects: strong evidence for the local carcinogenic action of acetaldehyde. Alcohol Clin Exp Res 2000;24:873–877. 33 Homann N, Kärkkäinen P, Koivisto T, Nosova T, Jokelainen K, Salaspuro M: Effects of acetaldehyde on cell regeneration and differentiation of the upper gastrointestinal tract mucosa. J Natl Cancer Inst 1997;89:1692–1697. 34 Simanowski UA, Suter PM, Stickel F, Maier H, Waldherr R, Smith D, Russel RM, Seitz HK: Oesophageal epithelial hyperregeneration following chronic ethanol ingestion: effect of age and salivary gland function. J Natl Cancer Inst 1993;85:2030–2033. 35 Homann N, Jousimies-Somer H, Jokelainen K, Heine R, Salaspuro M: High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis 1997; 18: 1739– 1743.

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36 Homann N, Tillonen J, Meurman J, Rintamaki H, Lindquist C, Rautio M, Jousimies-Somer H, Salaspuro M: Increased salivary acetaldehyde levels in heavy drinkers and smokers: a microbiological approach to oral cavity cancer. Carcinogenesis 2000;21:663–668. 37 Homann N, Tillonen J, Rintamaki H, Salaspuro M, Lindqvist C, Meurman JH: Poor dental status increases the acetaldehyde production from ethanol in saliva. A possible link to the higher risk of oral cancer among alcohol consumers. Oral Oncol 2001;37:153–158. 38 Simanowski UA, Seitz HK, Baier B, Kommerell B, Schmidt-Gayk H, Wright NA: Chronic ethanol consumption selectively stimulates rectal cell proliferation in the rat. Gut 196; 27: 278–282. 39 Lipkin M: Method for binary classiﬁcation and risk assessment of individuals with familial polyposis based on 3H-TdR labelling of epithelial cells in colonic crypts. Cell Tissue Kinet 1984;17:209–222. 40 Simanowski UA, Homann N, Knühl M, Arce C, Waldherr R, Conradt C, Bosch FX, Seitz HK: Increased rectal cell proliferation following alcohol abuse. Gut 2001;49:418–422. 41 Salaspuro M: Acetaldehyde, microbes, and cancer of the digestive tract. Crit Rev Clin Lab Sci 2003;40:183–208. 42 Oneta CM, Lieber CS, Li JJ, Ruttimann S, Schmid B, Lattmann J, Rosman AS, Seitz HK: Dynamics of cytochrome P4502E1 activity in men: induction by ethanol and disappearance during withdrawal phase. J Hepatol 2002; 36: 47–52. 43 Shimizu M, Lasker JM, Tsutsumi M, Lieber CS: Immunohistochemical localization of ethanol inducible cytochrome P4502E1 in rat alimentary tract. Gastroenterology 1990; 93: 1044–1050. 44 Baumgarten G, Waldherr R, Stickel F, Simanowski UA, Ingelmann-Sundberg M, Seitz HK: Enhanced expression of cytochrome P 4502E1 in the oropharyngeal mucosa of alcoholics with cancer (abstract). Annual Meeting International Society of Biomedical Researchers, Alcoholism, Washington, DC, June, 1996.

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45 Farinati F, Zhou Z, Bellah J, Lieber CS, Garro AJ: Effect of chronic ethanol consumption on activation of nitrosopyrrolidine to upper alimentary tract, lung and hepatic tissue. Drug Metab Dispos Biol 1985;13:210–216. 46 Sohn OA, Fiala ES, Puz C: Enhancement of rat liver microsomal metabolism of axozymethane to methylaxozymethanol by chronic ethanol administration: similarity to the microsomal metabolism of N-nitrosomethylamine. Cancer Res 1987;47:3123–3129. 47 Eskelson CD, Odeleye OE, Watson RR, Earnest DL, Mufti SI: Modulation of cancer growth by vitamin E and alcohol. Alcohol Alcohol 1993;28:117–126. 48 Vincon P, Wunderer J, Simanowski UA, Koll M, Preedy VR, Peters TJ, Werner J, Waldherr R, Seitz HK: Effect of ethanol and vitamin E on cell regeneration and BCL-2-expression in the colorectal mucosa of rats. Alcohol Clin Exp Res 2003;27:100–106. 49 Stickel F, Schuppan D, Hahn EG, Seitz HK: Effect of ethanol on hepatocarcinogenesis. Gut 2002;51:132–139. 50 Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC: Alcohol, lowmethionine-low folate diets and risk of colon cancer in men. J Natl Cancer Inst 1995; 87: 265–273. 51 Choi SW, Stickel F, Baik HW, et al: Chronic alcohol consumption induces genomic but not p53-speciﬁc DNA hypomethylation in rat colon. J Nutr 1999;129:1945–1950. 52 Barch DH, Kuemmerle SC, Holenberg PF, Iannacone PM: Oesophageal microsomal metabolism of N-nitrosomethylbenzylamine in the zinc deﬁcient rat. Cancer Res 1984; 44: 5629–5633. 53 Cho CH: Zinc: absorption and role in gastrointestinal metabolism and disorders. Dig Dis 1961;9:49–60.

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54 Wang XD, Liu C, Chung J, Stickel F, Seitz HK, Russell RM: Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-jun and c-fos) expression in rat liver. Hepatology 1998;28:744–750. 55 Chung IY, Liu C, Smith DE, Seitz HK, Russell RM, Wang XD: Restoration of retinoic acid concentration suppresses ethanol induced cjun overexpression and hepatocyte hyperproliferation in rat liver. Carcinogenesis 2001;22: 1213–1219. 56 Mobarhan S, Seitz HK, Russell RM, et al: Agerelated effects of chronic ethanol intake on vitamin A status in Fisher 344 rats. J Nutr 1991; 121:510–517. 57 Leo MA, Seitz HK, Maier H: Carotinoid, retinoid and vitamin E status of the oropharyngeal mucosa in the alcoholic. Alcohol Alcohol 1995; 30:163–170. 58 Liu C, Russell RM, Seitz HK, Wang XD: Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P4502E1. Gastroenterology 2001; 120:179–189. 59 Parlesak A, Menzl I, Feuchter A, et al: Inhibition of retinol oxidation by ethanol in the rat liver and colon. Gut 2000;47:825–831. 60 Seitz HK: Alcohol and retinoid metabolism. Gut 2000;47:748–750. 61 Albanes D, Heinonen OP, Taylor PR, Virtamo J, Edwards BK, Rautalahti M, Hartman AM, Palmgren J, Freedman LS, Haapakoski J, Barrett MJ, Pietinen P, Malila N, Tala E, Liippo K, Salomaa ER, Tangrea JA, Teppo L, Askin FB, Taskinen E, Erozan Y, Greenwald P, Huttunen JK: Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996;88:1560–1570. 62 Dan Z, Popov Y, Patsenker E, Preimel D, Liu C, Wang XD, Seitz HK, Schuppan D, Stickel F: Hepatotoxicity of alcohol-induced polar retinol metabolites involves apoptosis via loss of mitochondrial membrane potential. FASEB J 2005;19:1–4.

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Table 1. A choice of treatment possibilities

for alcohol-dependent patients Brief interventions, motivational therapy Qualiﬁed detoxiﬁcation Self-help groups for alcoholics Social therapy (counseling centers) Speciﬁc long-term treatment

Table 2. Flow chart for brief intervention practice and a set of

therapeutic skills to treat alcoholics (FRAMES) Brief interventions Medical diagnosis and feedback to the patient Give the patient information material One to three follow-up dates Methods (FRAMES) Feedback of personal risk and behavior Emphasis on Responsibility to change Give an Advice for change Give a Menu for alternative options Therapeutic Empathy as a counseling style Enhancement of client Self-efﬁcacy

targeted behavior. As such, brief interventions ﬁt very well within the clinical routine of general medical hospitals. Brief interventions can also be used to increase the referral rate to further treatment. If professionals only once recommend that alcohol-dependent patients should seek treatment, less than 5% of all patients usually following this advice. The success of brief interventions is greatly increased if, after a short delay, patients are contacted again, either by a member of the therapeutic team or the doctor himself, whether in writing or by a phone call, in which the professional expresses how much he cares for the patient and his alcohol problems and encourages him to seek treatment. Using brief interventions, successful referral can be achieved in up to 40% of all alcohol-dependent patients [3–5]. Most studies investigating the effect of brief interventions on excessive alcohol consumption did not use excessive diagnostic procedures to separate alcohol abusers from alcohol-dependent patients. Therefore, it is possible that those subjects, who meet the criteria for alcohol

Therapy and Supportive Care of Alcoholics: Guidelines for Practitioners

abuse, without yet having experienced a signiﬁcant reduction in their control of alcohol intake, may have gained most beneﬁt from this technique. In any case, a signiﬁcant reduction in alcohol intake by 10–30% has been observed in a series of studies [2–5]. This effect may not sound very impressive, however, it will drastically reduce the incidence of alcohol-related diseases, such as polyneuropathy or fatty liver and cirrhosis, at the level of the whole drinking population [6]. In case a patient needs repeated treatment with brief interventions, it is important to know that brief interventions are not likely to be successful if a strategy is used that has previously failed to affect alcohol intake and alcohol-related problems. However, there is good evidence that brief interventions should be provided for all alcohol-dependent patients that pass through a hospital setting. Major evidence leading to this conclusion comes from the observation that otherwise only a small number of alcohol-dependent patients will ﬁnd their way to speciﬁc treatments such as psychiatric detoxiﬁcation or further treatment programs. The percentage of patients who will join a speciﬁc treatment usually averages less than 8% of all alcoholics [7]. In contrast, the vast majority of this group, including about 80% of all alcohol-dependent patients, contact a general practitioner at least once a year and about 20–30% will be treated on non-psychiatric wards in the hospital, often for alcohol-associated physical problems. Brief intervention thus offers a way to help this majority of alcohol-dependent patients [2–5]. There is also no standard for the exact style of communication and content of brief interventions, despite the fact that some interventions have been shown to be of essential value. There is broad consensus that exact physical and psychological examination of the patient, as well as the professional feedback of the individual personal risk and impairment associated with alcohol abuse, may become important orientation markers for the patient. This feedback should focus on a detailed listing of the individual’s physical ﬁndings and alcohol-related problems and diseases, as well as on severe dysfunctional behavior, contributing heavily to the everyday problems of the patient. Brief interventions should also focus on the patient’s personal responsibility for change and provide clear advice for change. A very important detail in practicing the brief intervention technique is to respect the patient’s autonomy in decision-making but also to offer clear advice that the professional would suggest to do given his knowledge of the patient’s alcohol-related problems. The professional should then offer a variety of alternative change options, keeping in mind that some

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Table 3. Essential interventions in qualiﬁed detoxiﬁcation pro-

grams Three- to 4-week program Information on alcohol effects Therapeutic group sessions concerning alcohol dependence and relapse risk Stress reduction training Attending self-help groups

treatment options may be better suited to the patient’s individual life situation. As an interaction guideline another major instrument in this short psychotherapeutic intervention is therapeutic empathy and enhancement of the patient’s self-efﬁcacy or optimism [5, 8, 9]. The higher the patient’s self-efﬁcacy is, the more likely is his decision to remain abstinent. Although informing the patient about alcohol-induced organic and psychosocial comorbidities is mandatory, this intervention does not guarantee to affect treatment outcome. Patients that fail to change their behavior may be very well aware of the harmful consequences even after dramatic experiences. A much better predictor of the subsequent success of the patient’s efforts to remain abstinent is the patient’s self-efﬁcacy or the belief that he or she can cope with their alcohol-associated problems. In general an empathetic communication style is thought to be much more effective than confrontation with patients, blaming them for denying to face the harmful consequences of their alcohol problem.

Qualified Detoxification Programs

A major difﬁculty for the patients during detoxiﬁcation is to endure the negative withdrawal symptoms after long-term alcohol consumption. Especially during this time, they can be motivated for further treatment. The most encouraging and efﬁcient therapeutic procedure during alcohol detoxiﬁcation is a qualiﬁed treatment program (table 3). Such a program includes motivational sessions to encourage abstinence, psychosocial counseling and additional therapies such as the teaching of coping strategies, creative work or social skills training, and is rightfully labeled a ‘qualiﬁed detoxiﬁcation program’. These programs are considered the state-of-the-art in alcohol detoxiﬁcation [7, 10–12]. Several controlled studies have shown that qualiﬁed detoxiﬁcation over 3–8 weeks is successful in motivating

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patients for abstinence. About 50% of the population available for follow-up after 6–28 months were abstinent [13–15]. Even if all patients who were missing in the follow-up would have been counted as relapsers, the abstinence rate would still be impressive, ranging from 48% 6 months after detoxiﬁcation [13] to 32% when patients were assessed 28 months after termination of the qualiﬁed detoxiﬁcation program [15]. An important interface between all qualiﬁed detoxiﬁcation programs and self-help groups is a good cooperation with self-help groups as well as counseling and information centers, which are often part of the government health care institutions. In an effective disease management concept, hospital detoxiﬁcation is just one step in a chain of therapeutic interventions that will stabilize a patient to remain abstinent. In the hospital, patients should be informed that there are various therapeutic options available. Successful referral is also improved if patients join self-help groups or information counseling centers during their stay on the ward. From an economic point of view, qualiﬁed detoxiﬁcation signiﬁcantly reduces health costs due to a signiﬁcant reduction in alcohol-related expenses [16].

Polyclinics and Day-Care Clinics

Studies revealed that 30–50% of all alcohol-dependent patients suffer from comorbid psychiatric disorders such as depression or anxiety [17, 18]. If a patient with other psychiatric disorders has ceased alcohol consumption and decided to undergo further treatment, a speciﬁc treatment with regular consultations by a psychiatrist is mandatory. After detoxiﬁcation, there is a high incidence of mood disorders, most likely associated with a prolonged recovery of some monoaminergic systems [19, 20]. In some cases, treatment in day care clinics will be recommended [21–23]. An advantage of these institutions is that patients are very close to living their everyday life can but evaluate the burden of their disorder with their therapists. In a private environment, detoxiﬁed alcoholdependent patients are confronted with various alcoholspeciﬁc cues and typical drinking situations. During daycare treatment, new coping strategies can be trained in order to prepare for speciﬁc relapse-eliciting situations. During the whole time, treatment should include an attempt to solve ﬁnancial and social problems that accumulate during chronic alcohol intoxication.

Kienast/Heinz

Additional Psychopharmacological Treatment to Reduce the Relapse Rate

Craving for alcohol can be elicited by alcohol-associated cues. These cues are produced when an associative learning process has combined alcohol consumption with former neutral emotional or environmental stimuli [2, 24– 27]. Acamprosate, a drug used to reduce craving in abstinent alcoholics [27–31], inhibits glutamatergic NMDA receptor function and may exert its therapeutic effects by decreasing cue-induced alcohol craving [27–32]. Efﬁcacy studies have shown beneﬁts for patients treated with acamprosate. Here about 40% of all patients who received acamprosate remained abstinent, compared with 20% of all patients who received placebo. Another observation was that patients who received acamprosate remained longer in outpatient treatment and adjacent therapy such as selfhelp groups or counseling [27]. These results indicate a beneﬁt for patients treated with acamprosate. It has been suggested that especially those patients who tend to consume alcohol in stressful situations beneﬁt from acamprosate; however, this has to be proven in further studies. Alcohol craving might be increased due to the moodenhancing and often positive reinforcing effects of alcohol consumption [2, 24]. There is evidence that neuronal structures, like the so-called dopaminergic reward system and its opioidergic stimulation via -opiate receptors, play a special role in this mechanism [2, 19]. In some studies, naltrexone medication reduced the relapse risk of detoxiﬁed alcoholics [30, 33–37]. It has been suggested that naltrexone may work best in patients who mainly consume alcohol in positive situations, and who crave for the rewarding effects of alcohol [24, 33–37]. Again, this hypothesis awaits further testing.

Rehabilitation

In Germany and some other European countries, specialized rehabilitation clinics for alcohol-dependent patients offer long-term treatments and tend to treat alcohol-dependent patients for several weeks up to 3–6 months. Follow-up studies that evaluate the success rate of these clinics showed positive results for these treatment programs. Abstinence rates were measured 6 months to 1 year after treatment and ranged from 60 to 68% [38– 40]. Unfortunately, only a small percentage of alcoholdependent patients found their way to such clinics; in Germany, less than 2% of all alcohol-dependent patients undergo treatment in a stationary setting.

Therapy and Supportive Care of Alcoholics: Guidelines for Practitioners

Table 4. Criteria for alcohol dependence according to ICD-10

1 2 3 4 5 6

Development of tolerance to alcohol Withdrawal symptoms after alcohol intake has ceased Urgent demand to consume alcohol Loss or reduced control of alcohol intake Loss of interest in activities or hobbies Continuing alcohol consumption in spite of harmful consequences

Alcohol dependence can only be diagnosed if 3 of the 6 above named criteria are fulﬁlled within the last 12 months.

As an alternative, such rehabilitation programs can be carried out in a polyclinic setting. For example, the patients should participate at least once per week in therapeutic group therapy guided by an experienced psychotherapist. Furthermore, individual counseling is offered, usually at a rate of 1 h/week. In Germany, some outpatient concepts include outpatient rehabilitation that starts with daily counseling for 7 days, during which patients are detoxiﬁed and receive 3 psychotherapeutic counseling sessions according to the principles of motivational therapy. In such settings, 90% of all patients successfully completed detoxiﬁcation and 86% continued in further treatment programs. One year after the outpatient program started, 50% of all patients managed to remain abstinent and continued speciﬁc treatment [41–43].

Handling Patients with Low Abstinence Motivation

Some discussion remains as to whether patients should be trained to control their alcohol intake rather than to completely abstain from alcohol consumption. There is evidence that about 10% of all recently detoxiﬁed alcoholics continue to drink alcohol at a lower level than before treatment. It is important to note that two thirds of these patients either eventually succeed in sustaining their abstinence or slip into a more serious relapse. Altogether, moderate alcohol consumption has been found in only about 3% of all alcoholics in long-term follow-up studies. However, once a patient meets the criteria for alcohol dependence according to ICD-10 (table 4), especially the loss of control in drinking behavior, moderate drinking is not the intervention of choice [43]. Institutions that treat alcoholics should support patients who have not yet decided to remain abstinent, and

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therapists should accept that some patients only want to reduce alcohol intake. For this reason, treatment programs need to refer to the motivational state of a patient and then choose state-dependent therapeutic interventions. It is important to respect these ‘states of change’, even if abstinence is the recommendable choice for most alcoholics [44].

Detoxification and Patients Who Do Not Want to Abstain from Alcohol

In some hospitals patients who do not abstain from alcohol are neither counseled nor detoxiﬁed. Some settings even provide alcohol for such patients to avoid withdrawal symptoms and dysphoric and anxious mood states. This procedure violates one of the fundamental principals of medical care, namely not to harm the patient. For the patient, alcohol withdrawal in qualiﬁed settings should be used to motivate them for further treatment [42].

Conclusion

Alcoholism is a severe disorder that causes harm to the patients and elicits large costs in the healthcare system. Systematic interdisciplinary social, medical, and psychotherapeutic treatment is required to contact those patients before severe comorbidities appear. Even today alcoholics never enter qualiﬁed treatment programs; although they enter hospitals to treat the negative physical consequences of chronic alcohol intake. Every contact with the healthcare system offers a possibility for successful intervention. Using the technique of brief interventions, a cost-effective health intervention method with very good evidence for therapeutic success [5], one qualiﬁed counselor may have the capacity to provide care for numerous inpatients [7]. An adequate staff or liaison psychiatrist for brief interventions should be available in all general hospitals. Failing to provide this service would be comparable to treating acute hyperglycemia in diabetes while failing to counsel the patient on adequate diet and treat the underlying disease with insulin.

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