Editorial
Patterns of drinking and liver cirrhosis – What do we know and where do we go? Jürgen Rehm1,2,3,4,5,⇑, Michael Roerecke1 1 Centre for Addiction and Mental Health, 33 Russell Street, Toronto, ON M5S 2S1, Canada; 2Addiction Policy, Dalla Lana School of Public Health, University of Toronto, 155 College Street, 6th Floor, Toronto, ON M5T 3M7, Canada; 3Institute of Medical Science, University of Toronto, Faculty of Medicine, Medical Sciences Building, 1 King’s College Circle, Room 2374, Toronto, ON M5S 1A8, Canada; 4Department of Psychiatry, University of Toronto, 250 College Street, 8th Floor, Toronto, ON M5T 1R8, Canada; 5Institute of Clinical Psychology and Psychotherapy & Center of Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
See Article, pages 1061–1067
Askgaard and colleagues [1] contribute to our understanding of the etiology of liver cirrhosis in this issue of the Journal of Hepatology. This is a timely contribution about one of the most important, if not the most important, risk factors for liver cirrhosis globally [2], as our overall knowledge about drinking patterns and liver cirrhosis is sparse and in part contradictory. In fact, liver cirrhosis as a whole has been included into a recent listing of ‘‘forgotten’’ non-communicable diseases [3]. Where the ‘‘forgotten’’ referred to the somewhat arbitrary choice for the current Global Action Plan for the Prevention and Control of NonCommunicable Diseases by the World Health Organization (http://apps.who.int/iris/bitstream/10665/94384/1/97892415062 36_eng.pdf), but it could have also been referring to the lack of research on the etiology of alcoholic liver cirrhosis. The main contribution of Askgaard and colleagues [1] is threefold: first, they found that daily drinking was associated with the highest risk for liver cirrhosis; second, from a lifetime perspective, recent drinking as operationalized in the last decade, was more important compared to earlier drinking; and third, wine may have been associated with lower risk given the same amount of alcohol compared to beer or spirits. We will examine these three points separately. Ever since Lelbach’s seminal work in 1975 ([4]; see also the various contributions in [5]), the main school of thought has been that cirrhosis was a function of volume of alcohol consumed in a dose-response relationship irrespective of patterns of drinking. In the last systematic review on the topic, it was confirmed that average volume of alcohol intake was associated with liver cirrhosis in a dose-response relationship [6], and except for the work of Dawson and colleagues [7] which was based on a large representative survey in the US with only self-report of liver disease, no evidence for a differential effect from heavy drinking occasions
Received 12 January 2015; received in revised form 24 January 2015; accepted 27 January 2015 q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2014.12.005. ⇑ Corresponding author. Address: CAMH, 33 Russell Street, Toronto, ON M5S 2S1, Canada. Tel.: +1 416 535 8501x36173. E-mail address: [email protected] (J. Rehm).
was found in epidemiological studies. In other words, for the risk of liver cirrhosis, average volume of drinking seemed important and it presumably did not matter if 49 drinks a week were consumed as 7 drinks every day, or as 20 drinks each Friday and Saturday, and 9 drinks each Sunday, with no alcohol consumption during the other weekdays. However, animal studies would imply that the latter pattern of irregular binges may have an additional detrimental effect compared to people who do not binge drink [8]. This basic research (please see also [9]) seems to be in contrast to human epidemiological findings (see the early review of [10]), where a number of studies reported higher risks for daily drinkers compared to those who had days or periods of abstinence. Clearly, if overall volume of consumption is exactly the same, daily drinking in general implies less pronounced binges than non-daily drinking. The authors of the epidemiological studies [1,10] speculated that the lower risks of non-daily drinkers might be due to the possibility of the liver to regenerate itself during periods of abstinence, even if these periods were short. Lack of such periods of abstinence, i.e., lack of so-called ‘‘liver holidays’’, has also been claimed to be responsible for the higher all-cause mortality in people with daily drinking compared to people with less than daily drinking, adjusted for overall drinking volume in a Japanese study [11]. Unfortunately, most studies cited in the review of Parrish and colleagues [10] could not control fully for overall volume of alcohol consumed. In other words, it could be that daily drinkers also consumed overall more alcohol than non-daily drinkers, and that the higher overall volume was responsible for the higher risk of liver cirrhosis. The present study [1] controlled for this variable via regression, but non-linear effects may still have contributed to the finding. Moreover, the highest risks in the adjusted models were found for current abstainers, and this does not fit well with the regeneration hypothesis. Another problem with this hypothesis is that the Japanese results on patterns of drinking and allcause mortality based on the ‘‘liver holiday’’ hypothesis [11] could not be corroborated in the same cohort Askgaard and colleagues used, nor in other research (e.g., [12,13]). With regard to all-cause mortality, the difference seems to be that for the majority of the general population with mainly light to moderate drinking levels,
Journal of Hepatology 2015 vol. 62 j 1000–1001
JOURNAL OF HEPATOLOGY Table 1. Potential effect modification for mortality by total alcohol intake and drinking frequency.
Drinking frequency High Low
Average alcohol intake Moderate Heavy Lower risk Higher risk Higher risk Lower risk
Arrows show an increase in risk.
it is better to drink the same amount of alcohol spread out over more occasions, whereas for heavier drinking levels (in the Marugame study more than 43 g/day) the liver function becomes important and the reverse is true (please see Table 1). It is difficult to compare results for men and women in Askgaard and colleagues’ study [1]. Women drank less overall and in each of the frequency categories, and incidence of liver cirrhosis was lower than in men. Most of the sparse evidence for women points to a stronger effect of the same alcohol intake in women compared to men, as is the case for many other alcoholrelated disease outcomes. In addition, the highest risk for alcohol liver cirrhosis in women was for frequent but non-daily drinking, albeit with widely overlapping confidence intervals. While hormones and other gender-specific characteristics may play a role, it is also possible that ‘binge’ drinking is particularly associated with detrimental effects on the liver, either in combination with differential alcohol metabolism in women or as an independent risk factor. Only larger studies with enough power will help distinguish gender-specific risk profiles and potential interaction effects. Overall, more studies are needed to test the above hypothesis, which has implications for not only liver disease but also for low risk drinking guidelines. If it is true that for light to moderate drinkers, drinking free days may increase mortality risk (as seen in [12] or [13]), some of the advice in current drinking guidelines is questionable and should be re-examined. Obviously, there may be other considerations such as risk for alcohol use disorders in relation to frequency of drinking, but all-cause mortality clearly is an important outcome to consider for guidelines. On the other hand, for those who are drinking heavily, advice may be different, based on liver function. In order to give advice, health of the liver should be taken into consideration as well as better definition for heavy drinking should be empirically explored. The second finding of Askgaard and colleagues [1] about the importance of more recent drinking seems in line with ecological studies on liver cirrhosis or total mortality risk, which was evident following the reduction of alcohol supply such as the Gorbachev reform or the Germany invasion in Paris in the second World War or US prohibition (see [14] for an overview and references). Whenever alcohol was no longer available, liver cirrhosis mortality dropped considerably within a short time span [14]. The same phenomenon can be observed in time-series analyses, where changes in alcohol consumption lead to changes of liver cirrhosis in the same year ([15,16]; see [17] for a review of lag time of effects). While alcoholic liver cirrhosis is a chronic disease which develops over considerable time from the normal liver to steatosis and fibrosis to cirrhosis (http://www.easl.eu/assets/application/files/ 5e1b5512fb2cabb_file.pdf), a marked reduction of drinking or abstinence can delay mortality even if the disease is already at an advanced stage [10]. More individual level studies are necessary to further increase our understanding of this phenomenon. Finally, a third finding pointed to potential differences in mortality risk for different types of beverages with wine having being
associated with less risk [1]; however, again, with conflicting results regarding men and women. This result may be based on confounding variables associated with drinking wine in Denmark in the general population, as other studies in more homogeneous populations such as people with alcohol problems or alcohol use disorders, even in Denmark, did not support this conclusion [18,19]. Overall, the work of Askgaard and colleagues [1], as many good research does, not only increases our knowledge, but also raises questions for future research. The question of binge drinking patterns and mortality is far from solved, and there may be genetic differences or other covariates not yet discovered, which may also play a role and could explain the different empirical findings. Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Askgaard G, Grønbæk M, Kjaer MS, Tjønneland A, Tolstrup JS. Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study. J Hepatol 2015;62:1061–1067. [2] Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013;59:160–168. [3] Lopez AD, Williams TN, Levin A, Tonelli M, Singh JA, Burney PGJ, et al. Remembering the forgotten non-communicable diseases. BMC Med 2014;12:200. [4] Lelbach WK. Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Ann N Y Acad Sci 1975;252:85–105. [5] Hall P. Alcoholic liver disease – Pathobiology, epidemiology and clinical aspects. New York, USA: John Wiley & Sons; 1985. [6] Rehm J, Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, et al. Alcohol as a risk factor for liver cirrhosis – A systematic review and meta-analysis. Drug Alcohol Rev 2010;29:437–445. [7] Dawson DA, Li TK, Grant BF. A prospective study of risk drinking: at risk for what? Drug Alcohol Depend 2008;95:62–72. [8] Shukla SD, Pruett SB, Szabo G, Arteel GE. Binge ethanol and liver: new molecular developments. Alcohol Clin Exp Res 2013;37:550–557. [9] Mathurin P, Deltenre P. Effect of binge drinking on the liver: an alarming public health issue? Gut 2009;58:613–617. [10] Parrish KM, Higuchi S, Dufour MC. Alcohol consumption and the risk of developing liver cirrhosis: implications for future research. J Subst Abuse 1991;3:325–335. [11] Marugame T, Yamamoto S, Yoshimi I, Sobue T, Inoue M, Tsugane S. Patterns of alcohol drinking and all-cause mortality: results from a large-scale population-based cohort study in Japan. Am J Epidemiol 2007;165:1039–1046. [12] Tolstrup JS, Jensen MK, Tjonneland A, Overvad K, Gronbaek M. Drinking pattern and mortality in middle aged men and women. Addiction 2004;99:323–330. [13] Walsh G, Rehm J. Daily drinking and harm. Contemp Drug Probl 1996;23:465–478. [14] Rehm J, Roerecke M. Reduction of drinking in problem drinkers and all-cause mortality. Alcohol Alcohol 2013;48:509–513. [15] Norström T, Ramstedt M. Mortality and population drinking: a review of the literature. Drug Alcohol Rev 2005;24:537–547. [16] Zatonski W, Sulkowska U, Manczuk M, Rehm J, Lowenfels AB, La Vecchia C. Liver cirrhosis mortality in Europe, with special attention to central and eastern Europe. Eur Addict Res 2010;16:193–201. [17] Holmes J, Meier PS, Booth A, Guo Y, Brennan A. The temporal relationship between per capita alcohol consumption and harm: a systematic review of time lag specifications in aggregate time series analyses. Drug Alcohol Depend 2012;123:7–14. [18] Kamper-Jørgensen M, Grønbæk M, Tolstrup J, Becker U. Alcohol and cirrhosis: dose-response or threshold effect? J Hepatol 2004;41:25–30. [19] Pelletier S, Vaucher E, Aider R, Martin S, Perney P, Balmes JL, et al. Wine consumption is not associated with a decreased risk of alcoholic cirrhosis in heavy drinkers. Alcohol Alcohol 2002;37:618–621.
Journal of Hepatology 2015 vol. 62 j 1000–1001
1001
Patterns of drinking and liver cirrhosis – What do we know and where do we go? Jürgen Rehm1,2,3,4,5,⇑, Michael Roerecke1 1 Centre for Addiction and Mental Health, 33 Russell Street, Toronto, ON M5S 2S1, Canada; 2Addiction Policy, Dalla Lana School of Public Health, University of Toronto, 155 College Street, 6th Floor, Toronto, ON M5T 3M7, Canada; 3Institute of Medical Science, University of Toronto, Faculty of Medicine, Medical Sciences Building, 1 King’s College Circle, Room 2374, Toronto, ON M5S 1A8, Canada; 4Department of Psychiatry, University of Toronto, 250 College Street, 8th Floor, Toronto, ON M5T 1R8, Canada; 5Institute of Clinical Psychology and Psychotherapy & Center of Clinical Epidemiology and Longitudinal Studies (CELOS), Technische Universität Dresden, Chemnitzer Str. 46, 01187 Dresden, Germany
See Article, pages 1061–1067
Askgaard and colleagues [1] contribute to our understanding of the etiology of liver cirrhosis in this issue of the Journal of Hepatology. This is a timely contribution about one of the most important, if not the most important, risk factors for liver cirrhosis globally [2], as our overall knowledge about drinking patterns and liver cirrhosis is sparse and in part contradictory. In fact, liver cirrhosis as a whole has been included into a recent listing of ‘‘forgotten’’ non-communicable diseases [3]. Where the ‘‘forgotten’’ referred to the somewhat arbitrary choice for the current Global Action Plan for the Prevention and Control of NonCommunicable Diseases by the World Health Organization (http://apps.who.int/iris/bitstream/10665/94384/1/97892415062 36_eng.pdf), but it could have also been referring to the lack of research on the etiology of alcoholic liver cirrhosis. The main contribution of Askgaard and colleagues [1] is threefold: first, they found that daily drinking was associated with the highest risk for liver cirrhosis; second, from a lifetime perspective, recent drinking as operationalized in the last decade, was more important compared to earlier drinking; and third, wine may have been associated with lower risk given the same amount of alcohol compared to beer or spirits. We will examine these three points separately. Ever since Lelbach’s seminal work in 1975 ([4]; see also the various contributions in [5]), the main school of thought has been that cirrhosis was a function of volume of alcohol consumed in a dose-response relationship irrespective of patterns of drinking. In the last systematic review on the topic, it was confirmed that average volume of alcohol intake was associated with liver cirrhosis in a dose-response relationship [6], and except for the work of Dawson and colleagues [7] which was based on a large representative survey in the US with only self-report of liver disease, no evidence for a differential effect from heavy drinking occasions
Received 12 January 2015; received in revised form 24 January 2015; accepted 27 January 2015 q DOI of original article: http://dx.doi.org/10.1016/j.jhep.2014.12.005. ⇑ Corresponding author. Address: CAMH, 33 Russell Street, Toronto, ON M5S 2S1, Canada. Tel.: +1 416 535 8501x36173. E-mail address: [email protected] (J. Rehm).
was found in epidemiological studies. In other words, for the risk of liver cirrhosis, average volume of drinking seemed important and it presumably did not matter if 49 drinks a week were consumed as 7 drinks every day, or as 20 drinks each Friday and Saturday, and 9 drinks each Sunday, with no alcohol consumption during the other weekdays. However, animal studies would imply that the latter pattern of irregular binges may have an additional detrimental effect compared to people who do not binge drink [8]. This basic research (please see also [9]) seems to be in contrast to human epidemiological findings (see the early review of [10]), where a number of studies reported higher risks for daily drinkers compared to those who had days or periods of abstinence. Clearly, if overall volume of consumption is exactly the same, daily drinking in general implies less pronounced binges than non-daily drinking. The authors of the epidemiological studies [1,10] speculated that the lower risks of non-daily drinkers might be due to the possibility of the liver to regenerate itself during periods of abstinence, even if these periods were short. Lack of such periods of abstinence, i.e., lack of so-called ‘‘liver holidays’’, has also been claimed to be responsible for the higher all-cause mortality in people with daily drinking compared to people with less than daily drinking, adjusted for overall drinking volume in a Japanese study [11]. Unfortunately, most studies cited in the review of Parrish and colleagues [10] could not control fully for overall volume of alcohol consumed. In other words, it could be that daily drinkers also consumed overall more alcohol than non-daily drinkers, and that the higher overall volume was responsible for the higher risk of liver cirrhosis. The present study [1] controlled for this variable via regression, but non-linear effects may still have contributed to the finding. Moreover, the highest risks in the adjusted models were found for current abstainers, and this does not fit well with the regeneration hypothesis. Another problem with this hypothesis is that the Japanese results on patterns of drinking and allcause mortality based on the ‘‘liver holiday’’ hypothesis [11] could not be corroborated in the same cohort Askgaard and colleagues used, nor in other research (e.g., [12,13]). With regard to all-cause mortality, the difference seems to be that for the majority of the general population with mainly light to moderate drinking levels,
Journal of Hepatology 2015 vol. 62 j 1000–1001
JOURNAL OF HEPATOLOGY Table 1. Potential effect modification for mortality by total alcohol intake and drinking frequency.
Drinking frequency High Low
Average alcohol intake Moderate Heavy Lower risk Higher risk Higher risk Lower risk
Arrows show an increase in risk.
it is better to drink the same amount of alcohol spread out over more occasions, whereas for heavier drinking levels (in the Marugame study more than 43 g/day) the liver function becomes important and the reverse is true (please see Table 1). It is difficult to compare results for men and women in Askgaard and colleagues’ study [1]. Women drank less overall and in each of the frequency categories, and incidence of liver cirrhosis was lower than in men. Most of the sparse evidence for women points to a stronger effect of the same alcohol intake in women compared to men, as is the case for many other alcoholrelated disease outcomes. In addition, the highest risk for alcohol liver cirrhosis in women was for frequent but non-daily drinking, albeit with widely overlapping confidence intervals. While hormones and other gender-specific characteristics may play a role, it is also possible that ‘binge’ drinking is particularly associated with detrimental effects on the liver, either in combination with differential alcohol metabolism in women or as an independent risk factor. Only larger studies with enough power will help distinguish gender-specific risk profiles and potential interaction effects. Overall, more studies are needed to test the above hypothesis, which has implications for not only liver disease but also for low risk drinking guidelines. If it is true that for light to moderate drinkers, drinking free days may increase mortality risk (as seen in [12] or [13]), some of the advice in current drinking guidelines is questionable and should be re-examined. Obviously, there may be other considerations such as risk for alcohol use disorders in relation to frequency of drinking, but all-cause mortality clearly is an important outcome to consider for guidelines. On the other hand, for those who are drinking heavily, advice may be different, based on liver function. In order to give advice, health of the liver should be taken into consideration as well as better definition for heavy drinking should be empirically explored. The second finding of Askgaard and colleagues [1] about the importance of more recent drinking seems in line with ecological studies on liver cirrhosis or total mortality risk, which was evident following the reduction of alcohol supply such as the Gorbachev reform or the Germany invasion in Paris in the second World War or US prohibition (see [14] for an overview and references). Whenever alcohol was no longer available, liver cirrhosis mortality dropped considerably within a short time span [14]. The same phenomenon can be observed in time-series analyses, where changes in alcohol consumption lead to changes of liver cirrhosis in the same year ([15,16]; see [17] for a review of lag time of effects). While alcoholic liver cirrhosis is a chronic disease which develops over considerable time from the normal liver to steatosis and fibrosis to cirrhosis (http://www.easl.eu/assets/application/files/ 5e1b5512fb2cabb_file.pdf), a marked reduction of drinking or abstinence can delay mortality even if the disease is already at an advanced stage [10]. More individual level studies are necessary to further increase our understanding of this phenomenon. Finally, a third finding pointed to potential differences in mortality risk for different types of beverages with wine having being
associated with less risk [1]; however, again, with conflicting results regarding men and women. This result may be based on confounding variables associated with drinking wine in Denmark in the general population, as other studies in more homogeneous populations such as people with alcohol problems or alcohol use disorders, even in Denmark, did not support this conclusion [18,19]. Overall, the work of Askgaard and colleagues [1], as many good research does, not only increases our knowledge, but also raises questions for future research. The question of binge drinking patterns and mortality is far from solved, and there may be genetic differences or other covariates not yet discovered, which may also play a role and could explain the different empirical findings. Conflict of interest The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. References [1] Askgaard G, Grønbæk M, Kjaer MS, Tjønneland A, Tolstrup JS. Alcohol drinking pattern and risk of alcoholic liver cirrhosis: a prospective cohort study. J Hepatol 2015;62:1061–1067. [2] Rehm J, Samokhvalov AV, Shield KD. Global burden of alcoholic liver diseases. J Hepatol 2013;59:160–168. [3] Lopez AD, Williams TN, Levin A, Tonelli M, Singh JA, Burney PGJ, et al. Remembering the forgotten non-communicable diseases. BMC Med 2014;12:200. [4] Lelbach WK. Cirrhosis in the alcoholic and its relation to the volume of alcohol abuse. Ann N Y Acad Sci 1975;252:85–105. [5] Hall P. Alcoholic liver disease – Pathobiology, epidemiology and clinical aspects. New York, USA: John Wiley & Sons; 1985. [6] Rehm J, Taylor B, Mohapatra S, Irving H, Baliunas D, Patra J, et al. Alcohol as a risk factor for liver cirrhosis – A systematic review and meta-analysis. Drug Alcohol Rev 2010;29:437–445. [7] Dawson DA, Li TK, Grant BF. A prospective study of risk drinking: at risk for what? Drug Alcohol Depend 2008;95:62–72. [8] Shukla SD, Pruett SB, Szabo G, Arteel GE. Binge ethanol and liver: new molecular developments. Alcohol Clin Exp Res 2013;37:550–557. [9] Mathurin P, Deltenre P. Effect of binge drinking on the liver: an alarming public health issue? Gut 2009;58:613–617. [10] Parrish KM, Higuchi S, Dufour MC. Alcohol consumption and the risk of developing liver cirrhosis: implications for future research. J Subst Abuse 1991;3:325–335. [11] Marugame T, Yamamoto S, Yoshimi I, Sobue T, Inoue M, Tsugane S. Patterns of alcohol drinking and all-cause mortality: results from a large-scale population-based cohort study in Japan. Am J Epidemiol 2007;165:1039–1046. [12] Tolstrup JS, Jensen MK, Tjonneland A, Overvad K, Gronbaek M. Drinking pattern and mortality in middle aged men and women. Addiction 2004;99:323–330. [13] Walsh G, Rehm J. Daily drinking and harm. Contemp Drug Probl 1996;23:465–478. [14] Rehm J, Roerecke M. Reduction of drinking in problem drinkers and all-cause mortality. Alcohol Alcohol 2013;48:509–513. [15] Norström T, Ramstedt M. Mortality and population drinking: a review of the literature. Drug Alcohol Rev 2005;24:537–547. [16] Zatonski W, Sulkowska U, Manczuk M, Rehm J, Lowenfels AB, La Vecchia C. Liver cirrhosis mortality in Europe, with special attention to central and eastern Europe. Eur Addict Res 2010;16:193–201. [17] Holmes J, Meier PS, Booth A, Guo Y, Brennan A. The temporal relationship between per capita alcohol consumption and harm: a systematic review of time lag specifications in aggregate time series analyses. Drug Alcohol Depend 2012;123:7–14. [18] Kamper-Jørgensen M, Grønbæk M, Tolstrup J, Becker U. Alcohol and cirrhosis: dose-response or threshold effect? J Hepatol 2004;41:25–30. [19] Pelletier S, Vaucher E, Aider R, Martin S, Perney P, Balmes JL, et al. Wine consumption is not associated with a decreased risk of alcoholic cirrhosis in heavy drinkers. Alcohol Alcohol 2002;37:618–621.
Journal of Hepatology 2015 vol. 62 j 1000–1001
1001
