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Global burden of alcoholic liver diseases

  • Jürgen Rehm
    Correspondence
    Corresponding author. Address: Centre for Addiction and Mental Health (T 505), 33 Russell Street, Toronto, Ontario, Canada M5S 2S1. Tel.: +1 416 535 8501x6173.
    Affiliations
    Social and Epidemiological Research (SER) Department, Centre for Addiction and Mental Health, Toronto, Canada

    Dalla Lana School of Public Health, University of Toronto, Canada

    Department of Psychiatry, Faculty of Medicine, University of Toronto, Canada

    PAHO/WHO Collaborating Centre for Mental Health & Addiction, Dresden, Germany

    Technische Universität Dresden, Klinische Psychologie & Psychotherapie, Dresden, Germany

    Institute of Medical Science, University of Toronto, Canada
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  • Andriy V. Samokhvalov
    Affiliations
    Social and Epidemiological Research (SER) Department, Centre for Addiction and Mental Health, Toronto, Canada

    Department of Psychiatry, Faculty of Medicine, University of Toronto, Canada
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  • Kevin D. Shield
    Affiliations
    Social and Epidemiological Research (SER) Department, Centre for Addiction and Mental Health, Toronto, Canada

    Institute of Medical Science, University of Toronto, Canada
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Open AccessPublished:March 18, 2013DOI:https://doi.org/10.1016/j.jhep.2013.03.007

      Summary

      Liver diseases contribute markedly to the global burden of mortality and disease. This paper provides an overview from a global perspective of the contribution of alcohol to liver diseases.
      The Global Burden of Disease study methodology was used to estimate the burden of alcohol-attributable liver cirrhosis and alcohol-attributable liver cancer in 2010 as measured by deaths and disability adjusted life years (DALYs). This methodology estimates attributable fractions based on alcohol exposure distribution and relative risks associated with different levels of drinking.
      Globally, in 2010, alcohol-attributable liver cirrhosis was responsible for 493,300 deaths (156,900 female deaths and 336,400 male deaths) and 14,544,000 DALYs (4,112,000 DALYs for women and 10,432,000 DALYs for men), representing 0.9% (0.7% for women and 1.2% for men) of all global deaths and 0.6% (0.4% for women and 0.8% for men) of all global DALYs, and 47.9% of all liver cirrhosis deaths (46.5% for women and 48.5% for men) and 46.9% of all liver cirrhosis DALYs (44.5% for women and 47.9% for men). Alcohol-attributable liver cancer was responsible for 80,600 deaths (14,800 female deaths and 65,900 male deaths) and 2,142,000 DALYs (335,000 DALYs for women and 1,807,000 DALYs for men).
      The burden of alcohol-attributable liver cirrhosis and liver cancer is high and entirely preventable. Interventions to reduce alcohol consumption are recommended as a population health priority and may range from taxation increases for alcoholic beverages to increases in screening and treatment rates for alcohol use disorders.

      Abbreviations:

      ALD (alcoholic liver disease), DALYs (disability adjusted life years), ICD (international classification of diseases), GBD (global burden of disease), PYLL (potential years of life lost), YLD (years lived with disability), AAF (alcohol-attributable fraction), RR (relative risk), USD (US dollars)

      Keywords

      Introduction

      The global burden of liver diseases

      Liver diseases have been found to contribute markedly to the global burden of mortality and morbidity [
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Murray C.J.L.
      • Vos T.
      • Lozano R.
      • Naghavi M.
      • Flaxman A.D.
      • Michaud C.
      • et al.
      Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ]. In the 2010 Global Burden of Disease (GDB) study, more than one million deaths (1,030,800 deaths representing 2.0% of all deaths, 1.4% of all deaths of women and 2.4% of all deaths of men) and 31,027,000 Disability Adjusted Life Years (DALYs) (1.2% of all DALYs, 0.8% of all DALYs for women, 1.6% of all DALYs for men) were due to liver cirrhosis. A DALY here denotes a summary measure for burden of disease, which is composed of the addition of years of life lost to premature mortality and years of life lost to disability. Another 752,100 deaths (representing 1.4% of all deaths, 1.0% of all deaths of women and 1.8% of all deaths of men) and 19,111,000 DALYs (0.8% of all DALYs, 0.5% of all DALYs for women and 1.0% of all DALYs for men) were due to liver cancer. The health burden for both diseases is considerably more pronounced in men with 67% of liver cirrhosis deaths and 69% of liver cancer deaths involving men, and 70% of DALYs due to liver cirrhosis and 73% of DALYs due to liver cancer in each case for men.

      Alcohol and liver disease

      Alcohol is consumed widely in most parts of the world and has long been identified as a major risk factor for all liver diseases [
      • Rush B.
      An inquiry into the effects of ardent spirits upon the human body and mind: with an account of the means of preventing, and of the remedies for curing them.
      ]; for modern overviews see [
      • Rehm J.
      • Baliunas D.
      • Borges G.L.G.
      • Graham K.
      • Irving H.M.
      • Kehoe T.
      • et al.
      The relation between different dimensions of alcohol consumption and burden of disease – an overview.
      ,
      • 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.
      ,
      • International Agency for Research on Cancer
      Alcohol consumption and ethyl carbamate. Monograph 96 on the evaluation of carcinogenic risks to humans.
      ]. Even though the majority of adults are still abstainers, almost half of the world’s population consumed alcohol in the past year [
      • World Health Organization
      Global status report on alcohol and health.
      ]. It is the aim of this paper to provide an overview from a global perspective of the contribution of alcohol to liver diseases.

      Alcoholic liver disease – pathology and biological pathways

      The International Classification of Diseases (ICD-10) recognizes several forms of alcoholic liver disease (ALD; see ICD-10, K70), sometimes considered stages [
      • O’Shea R.S.
      • Dasarathy S.
      • McCullough A.J.
      • Practice Guideline Committee of the American Association for the Study of Liver Diseases
      • Practice Parameters Committee of the American College of Gastroenterology
      Alcoholic liver disease.
      ], that range from relatively mild and reversible alcoholic hepatic steatosis (fatty liver) (K70.0) and alcoholic hepatitis (K70.1), to alcoholic fibrosis and sclerosis of the liver (K70.2), and further to severe and irreversible stages of ALD, such as alcoholic liver cirrhosis (K70.3) and alcoholic hepatic failure (K70.4).
      Pathogenesis of specific forms of ALD is covered extensively in the EASL Clinical Practical Guidelines for the management of ALD [
      • European Association for the Study of the Liver
      EASL clinical practical guidelines: management of alcoholic liver disease.
      ]. In short, alcohol consumption, especially heavy consumption, induces changes in lipid metabolism (increases lipogenesis and mobilization of lipids and simultaneously decreases hepatic lipid catabolism), resulting in accumulation of lipids in hepatocytes called fatty liver. In some cases, alcohol consumption causes an inflammatory response, known as alcoholic hepatitis or steatohepatitis if it is accompanied by hepatic lipid deposition. Though hepatic steatosis and alcoholic hepatitis do not normally cause irreversible hepatocellular changes, persistence and severity of these conditions eventually lead to fibrosis and sclerotic changes in the liver that result in liver cirrhosis due to insidious replacement of hepatocytes with connective tissue, and subsequent liver failure.
      Diagnosis of ALD is based on various clinical and laboratory findings and confirmation of alcohol as the etiological factor [
      • Levitsky J.
      • Mailliard M.E.
      Diagnosis and therapy of alcoholic liver disease.
      ,
      • Menon K.V.
      • Gores G.J.
      • Shah V.H.
      Pathogenesis, diagnosis, and treatment of alcoholic liver disease.
      ]. Clinical symptoms of ALD vary from asymptomatic hepatic steatosis to malaise, anorexia, weight loss, abdominal discomfort, tender hepatomegaly, jaundice, and remote sequelae of liver dysfunction characteristic of more advanced forms of disease. Differentiation between ALD and liver disease not due to alcohol consumption is often made by a history of regular alcohol consumption above the threshold of 20 grams of pure ethanol per day for women and 30 grams of pure alcohol per day for men [
      • European Association for the Study of the Liver
      EASL clinical practical guidelines: management of alcoholic liver disease.
      ,
      • Adams L.A.
      • Angulo P.
      • Lindor K.D.
      Nonalcoholic fatty liver disease.
      ]; however, the risk curve between the level of alcohol consumption and liver disease is exponential, so ALD is more often associated with much higher levels of consumption [
      • 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.
      ,
      • Dawson D.A.
      • Li T.K.
      • Grant B.F.
      A prospective study of risk drinking: at risk for what?.
      ,
      • Corrao G.
      • Arico S.
      • Carle F.
      • Russo R.
      • Galatola G.
      • Tabone M.
      • et al.
      A case-control study on alcohol consumption and the risk of chronic liver disease.
      ]. Laboratory findings can be used to describe the severity of ALD and might be indicative of recent alcohol consumption. Differentiation between the forms of ALD is based on specific imaging or histological findings [
      • Bird G.L.
      Investigation of alcoholic liver disease.
      ,
      • Lefkowitch J.H.
      Morphology of alcoholic liver disease.
      ]; for a more detailed description see [
      • European Association for the Study of the Liver
      EASL clinical practical guidelines: management of alcoholic liver disease.
      ].
      In addition, consumption of alcohol can also cause liver cancer through similar biological pathways [
      • International Agency for Research on Cancer
      Alcohol consumption and ethyl carbamate. Monograph 96 on the evaluation of carcinogenic risks to humans.
      ]. This condition will be discussed later in our review.

      Organization of the paper

      We start with an overview of available data at the global level, and with the methodology used to estimate the proportion of the health burden caused by alcohol-attributable liver cirrhosis and liver cancer. After presenting the results of our estimations, we discuss potential interventions to reduce the burden of ALDs, and the implications of these interventions.

      Materials and methods

      Global data availability

      While alcoholic liver cirrhosis and other ALDs constitute a large portion of all liver disease (e.g., more than 75% of all liver cirrhosis in the European Union in 2004 was estimated to be caused by alcohol [
      • Rehm J.
      • Shield K.D.
      • Rehm M.X.
      • Gmel Jr., G.
      • Frick U.
      Alcohol consumption, alcohol dependence, and attributable burden of disease in Europe: potential gains from effective interventions for alcohol dependence.
      ]; for earlier estimates of global figures see [
      • Rehm J.
      • Room R.
      • Monteiro M.
      • Gmel G.
      • Graham K.
      • Rehn N.
      • et al.
      Alcohol use.
      ]), the incidence of ALDs cannot be reliably estimated for all regions of the world as causes of death are often based on verbal autopsies, which remain the main method underlying global mortality statistics [
      • Murray C.J.
      • Lopez A.D.
      • Black R.
      • Ahuja R.
      • Ali S.M.
      • Baqui A.
      • et al.
      Population Health Metrics Research Consortium gold standard verbal autopsy validation study: design, implementation, and development of analysis datasets.
      ,
      • Lopez A.D.
      • Mathers C.D.
      • Ezzati M.
      • Jamison D.T.
      • Murray C.J.L.
      Global burden of disease and risk factors.
      ]. In fact, ALDs cannot be reliably estimated in the small number of countries with vital registries, as the assessment of whether a liver disease is due to alcohol consumption or otherwise is highly impacted by socio-cultural factors. For instance, in their seminal study in 12 cities in 10 countries, Puffer and Griffith [
      • Puffer R.R.
      • Griffith G.W.
      Patterns of urban mortality: report of the inter-American investigation of mortality.
      ] found that after triangulating data on death certificates with data from hospital records and interviews (attending physicians, family members), the number of deaths assigned to alcoholic liver cirrhosis more than doubled, with the majority of new cases being re-coded from categories of cirrhosis which do not mention alcohol. This under-reporting has persisted in later studies [
      • Haberman P.W.
      • Weinbaum D.F.
      Liver cirrhosis with and without mention of alcohol as cause of death.
      ], and seems to be the case for all alcohol-attributable disease categories [
      • Pollock D.A.
      • Boyle C.A.
      • DeStefano F.
      • Moyer L.A.
      • Kirk M.L.
      Underreporting of alcohol-related mortality on death certificates of young U.S. army veterans.
      ] which are impacted by stigma, including, but not limited to, the disclosure of heavy alcohol consumption and alcohol use disorders [
      • Schomerus G.
      • Lucht M.
      • Holzinger A.
      • Matschinger H.
      • Carta M.G.
      • Angermeyer M.C.
      The stigma of alcohol dependence compared with other mental disorders: a review of population studies.
      ]. As one consequence, alcohol use disorders are currently the least treated mental disorder [
      • Kohn R.
      • Saxena S.
      • Levav I.
      • Saraceno B.
      The treatment gap in mental health care.
      ,
      • Rehm J.
      • Shield K.D.
      • Rehm M.X.
      • Gmel G.
      • Frick U.
      Modelling the impact of alcohol dependence on mortality burden and the effect of available treatment interventions in the European Union.
      ].
      The 2010 GBD study attempted estimates of liver cirrhosis and cancer “secondary to alcohol use” [
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Murray C.J.L.
      • Vos T.
      • Lozano R.
      • Naghavi M.
      • Flaxman A.D.
      • Michaud C.
      • et al.
      Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Vos T.
      • Flaxman A.D.
      • Naghavi M.
      • Lozano R.
      • Michaud C.
      • Ezzati M.
      • et al.
      Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ]. While the methods used to calculate these estimates were not part of the publications, the limitations specified above apply, and should be kept in mind when interpreting the data. For the specific secondary causes of liver cirrhosis and liver cancer, liver cirrhosis secondary to alcohol use for 2010 was estimated to be 282,800 deaths and 8,575,000 DALYs (representing 19.8% and 19.8% of all liver cirrhosis deaths and DALYs in 2010, respectively). The mortality and DALYs from liver cancer secondary to alcohol for 2010 was estimated to be 149,000 deaths and 3,782,000 DALYs (representing 27.4% and 27.6% of all liver cirrhosis deaths and DALYs in 2010, respectively). The full burden of liver cirrhosis and liver cancer attributable to alcohol is not reflected in the deaths or DALYs secondary to alcohol use, as specified. Not only is there a stigma attached to the labelling of heavy alcohol use or abuse as a cause of disease or mortality, but such alcohol consumption often interacts with other secondary causes of death, such as hepatitis B. Thus, a person, who develops liver disease secondary to hepatitis B and who consumes alcohol while living with the disease, has a markedly increased risk of mortality compared to a person who develops liver disease secondary to hepatitis B but abstains from alcohol consumption. As a result, some of the burden of liver disease secondary to hepatitis B, hepatitis C, or other causes is attributable to alcohol (i.e., outcomes, that would not have occurred if alcohol had not been consumed [
      • Rehm J.
      • Taylor B.
      • Patra J.
      • Gmel G.
      Avoidable burden of disease: conceptual and methodological issues in substance abuse epidemiology.
      ,
      • Walter S.D.
      The estimation and interpretation of attributable risk in health research.
      ]).
      Given the lack of reliable direct estimates of mortality and the burden of disease due to ALD, we estimated the burden of alcohol-attributable liver cirrhosis indirectly using standard epidemiological methodology. We used the respective GBD study category for liver cirrhosis, which comprises all of the K70 codes, and estimated the proportion of alcohol-attributable liver cirrhosis based on the prevalence of alcohol consumption and the risk relations between levels of consumption and the disease outcomes (for details see the next section).

      Data sources and statistical model

      To estimate the number of deaths, potential years of life lost (PYLL), years lived with disability (YLD), and DALYs from liver cirrhosis and liver cancer that are attributable to alcohol consumption, we combined the risks of each of liver cirrhosis and liver cancer with the prevalence of alcohol exposure using alcohol-attributable fractions (AAF) calculated using the 2010 GBD study methodology [

      Institute for Health Metrics Evaluation. GBD operations manual final draft. 2011 http://www.who.int/healthinfo/global_burden_disease/GBD_2005_study/en/index.html.

      ,
      • Lim S.S.
      • Vos T.
      • Flaxman A.D.
      • Danaei G.
      • Shibuya K.
      • Adair-Rohani H.
      • et al.
      A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ]. AAFs represent the proportion of each outcome that would not have occurred in a counterfactual scenario where no one consumes alcohol (see [
      • Walter S.D.
      The estimation and interpretation of attributable risk in health research.
      ,
      • Benichou J.
      A review of adjusted estimators of attributable risk.
      ] for more information on attributable fractions). The method to calculate the number of deaths, PYLL, YLD, and DALYs attributable to alcohol consumption has two main steps: (1) calculation of the race-, age-, sex-, and consumption-specific AAFs, and then (2) application of these AAFs to the corresponding mortality, PYLL, YLD, and DALYs data (see [
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Murray C.J.L.
      • Vos T.
      • Lozano R.
      • Naghavi M.
      • Flaxman A.D.
      • Michaud C.
      • et al.
      Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Vos T.
      • Flaxman A.D.
      • Naghavi M.
      • Lozano R.
      • Michaud C.
      • Ezzati M.
      • et al.
      Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ] for an overview of GBD study procedures to calculate these outcome indicators). For details on the model please see the section on statistical models below.
      All data were available by age and sex at the regional level. Regions were defined in accordance with the 2010 GBD study [

      Institute for Health Metrics Evaluation. GBD operations manual final draft. 2011 http://www.who.int/healthinfo/global_burden_disease/GBD_2005_study/en/index.html.

      ]. Grouping of countries into regions was determined by geographical location and epidemiological profile (child and adult mortality levels and major causes of death). Neither income nor population of the countries in a region had an impact on the grouping structure. The countries included within each GBD region are described in Supplementary data 1.

      Alcohol consumption data

      Data on alcohol consumption and drinking patterns were obtained for 2005 and estimated for 2010 (see [

      Shield KD, Rylett M, Gmel G, Gmel G, Kehoe-Chan TA, Rehm J. Global alcohol exposure estimates by country, territory and region for 2005 – a contribution to the Comparative Risk Assessment for the 2010 Global Burden of Disease Study. Addiction 2013 Jan 24 [Epub ahead of print]. http://dx.doi.org/10.1111/add.12112.

      ] for country- and region-specific data on alcohol consumption and patterns). Data for recorded, unrecorded and tourist per capita consumption of pure alcohol (ethanol) were obtained from the Global Information System on Alcohol and Health [
      • World Health Organization
      Global information system on alcohol and health.
      ] based on surveys conducted by the WHO and regularly published in the Global Status Reports on Alcohol and Health (for the most recent report see: [
      • World Health Organization
      Global status report on alcohol and health.
      ]). The prevalence of lifetime abstainers (people who have never consumed one standard drink of alcohol), former drinkers (people who have consumed alcohol but have not done so within the past year), and current drinkers were obtained from large, nationally representative surveys in the respective countries [

      Shield KD, Rylett M, Gmel G, Gmel G, Kehoe-Chan TA, Rehm J. Global alcohol exposure estimates by country, territory and region for 2005 – a contribution to the Comparative Risk Assessment for the 2010 Global Burden of Disease Study. Addiction 2013 Jan 24 [Epub ahead of print]. http://dx.doi.org/10.1111/add.12112.

      ].
      Alcohol consumption was modeled using data on per capita consumption triangulated with data on the prevalence of current drinkers and using methods described elsewhere [
      • Rehm J.
      • Kehoe T.
      • Gmel G.
      • Stinson F.
      • Grant B.
      • Gmel G.
      Statistical modeling of volume of alcohol exposure for epidemiological studies of population health: the example of the US.
      ,
      • Kehoe T.
      • Gmel G.
      • Shield K.
      • Gmel G.
      • Rehm J.
      Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms.
      ].

      Mortality data

      Data on the number of deaths, PYLL, YLD, and DALYs for all causes, malignant neoplasms (ICD-10 codes: C00–C97), liver cirrhosis (K70 and K74), and liver cancer (C22) were obtained from the 2010 GBD study [
      • Lozano R.
      • Naghavi M.
      • Foreman K.
      • Lim S.
      • Shibuya K.
      • Aboyans V.
      • et al.
      Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Murray C.J.L.
      • Vos T.
      • Lozano R.
      • Naghavi M.
      • Flaxman A.D.
      • Michaud C.
      • et al.
      Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Vos T.
      • Flaxman A.D.
      • Naghavi M.
      • Lozano R.
      • Michaud C.
      • Ezzati M.
      • et al.
      Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ].

      Risks of liver cancer and liver cirrhosis

      Relative risk (RR) estimates for liver cirrhosis were obtained from a meta-analysis performed by Rehm and colleagues [
      • 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.
      ] and the RR estimates for liver cancer were obtained from a meta-analysis performed by Corrao and colleagues [
      • Corrao G.
      • Bagnardi V.
      • Zambon A.
      • La Vecchia C.
      A meta-analysis of alcohol consumption and the risk of 15 diseases.
      ] (see Supplementary data 2 for graphs of the RR functions differentiated by sex for liver cirrhosis and liver cancer).

      Statistical modeling

      The following formula was used to derive the AAF:
      AAF=Pabstainers+PFormer_drinkersRRFormer_drinkers+>0150PCurrent_drinkers(x)RRCurrent_drinkers(x)-1Pabstainers+PFormer_drinkersRRFormer_drinkers+>0150PCurrent_drinkers(x)RRCurrent_drinkers(x)


      where Pabstainers, PFormer_drinkers and PCurrent_drinkers (x) represent the prevalence of abstainers, former drinkers and current drinkers (given an average daily alcohol consumption of x), respectively. RRFormer_drinkers and RRCurrent_drinkers (x) represent the risk of liver cirrhosis or liver cancer for former drinkers and current drinkers (given an average daily alcohol consumption of x) relative to the risk of liver cirrhosis or liver cancer for lifetime abstainers. For more information on how AAFs are calculated see [
      • Kehoe T.
      • Gmel Jr., G.
      • Shield K.
      • Gmel Sr., G.
      • Rehm J.
      Determining the best population-level alcohol consumption model and its impact on estimates of alcohol-attributable harms.
      ].
      Age- and sex-specific population data for 2010 were obtained from the 2010 GBD study based on UN Population Division estimates. Standardized mortality rates were calculated based on the global population structure.

      Association between alcohol-attributable harms and gross domestic product

      A linear regression was employed (weighted for population size) to investigate the association between the number of alcohol-attributable liver cirrhosis and liver cancer deaths and DALYs per 100,000 people per litre of alcohol consumed per capita, and gross domestic product adjusted for purchase power parity (GDP (PPP)). Data on GDP (PPP) for 2010 (measured in current US dollars) was obtained from The World Bank [
      • The World Bank
      World Data Bank, world development indicators.
      ].

      Results

      Global alcohol consumption

      Fig. 1 outlines the adult per capita consumption of alcohol by country for 2010. Eastern Europe had the highest per capita consumption, with 15.7 L per person (8.1 L per woman and 24.9 L per man), while the GBD region of North Africa/Middle East had the lowest adult per capita consumption of alcohol, with 1.0 L per person (0.2 L per woman and 1.7 L per man). Southern Sub-Saharan Africa had the highest per drinker consumption of alcohol, with 30.3 L of alcohol consumed per drinker in 2010 (37.8 L per man and 23.0 L per woman). Eastern Europe had the highest pattern of drinking score at 4.9, indicating that people in that region consumed large quantities of alcohol frequently, often drank to intoxication, engaged in prolonged binges, and consumed alcohol mainly outside of meals [
      • Popova S.
      • Rehm J.
      • Patra J.
      • Zatonski W.
      Comparing alcohol consumption in central and eastern Europe to other European countries.
      ,
      • Nemtsov A.V.
      A contemporary history of alcohol in Russia.
      ]; for a definition of patterns of drinking score, see Rehm et al. [
      • Rehm J.
      • Rehn N.
      • Room R.
      • Monteiro M.
      • Gmel G.
      • Jernigan D.
      • et al.
      The global distribution of average volume of alcohol consumption and patterns of drinking.
      ].
      Figure thumbnail gr1
      Fig. 1Total adult per capita consumption, in litres of pure alcohol, 2010.

      Global burden of liver cirrhosis

      As indicated above, in 2010 liver cirrhosis was responsible for 1,030,800 deaths and for 31,027,000 DALYs lost. Of all deaths caused by liver cirrhosis, 493,300 deaths were alcohol-attributable (47.9% of all liver cirrhosis deaths), representing 0.9% of all deaths due to any cause (0.7% of all deaths of women and 1.2% of all deaths of men). Of the net burden of disease of mortality attributable to alcohol consumption in 2010, alcohol-attributable liver cirrhosis was responsible for 10.4% of this burden (9.3% for women and 11.0% for men). Table 1 outlines the number of deaths from liver cirrhosis that are attributable to alcohol consumption, the percentage of all deaths that were due to alcohol-attributable liver cirrhosis, and the percentage of all alcohol-attributable deaths that were due to liver cirrhosis.
      Table 1Alcohol-attributable deaths caused by liver cirrhosis in 2010.
      Globally, in 2010 7.2 deaths per 100,000 people (4.6 deaths per 100,000 females and 9.7 deaths per 100,000 males) were caused by liver cirrhosis attributable to alcohol consumption. Fig. 2 displays the number of liver cirrhosis deaths per 100,000 people, attributable to alcohol consumption differentiated by sex and region. Central Asia experienced the greatest number of alcohol-attributable liver cirrhosis deaths per 100,000 people, with 17.5 deaths per 100,000 people (14.6 deaths per 100,000 women, and 20.4 deaths per 100,000 men). Central Latin America had the second highest rate of alcohol-attributable deaths due to liver cirrhosis, with 15.8 deaths per 100,000 people (7.8 deaths per 100,000 women, and 23.6 deaths per 100,000 men).
      Figure thumbnail gr2
      Fig. 2Alcohol-attributable liver cirrhosis deaths per 100,000 people in 2010 by sex and region.
      The number of deaths from liver cirrhosis (corrected for population size) attributable to alcohol consumption was much greater among people 65 years of age and older (31.1 deaths per 100,000 people) when compared to people 15–34 years of age (1.0 deaths per 100,000 people) and people 35–64 years of age (13.1 deaths per 100,000 people). This relationship between alcohol-attributable deaths from liver cirrhosis and age was observed for both men and women. In terms of relative contributions, the impact of alcoholic liver cirrhosis is the greatest in the middle age group: 4.9%, 62.1%, and 33.0% of all deaths from alcohol-attributable liver cirrhosis occurred in people aged 15–34, 35–64, and 65 years and older, respectively.
      Of all DALYs due to liver cirrhosis 14,544,000 DALYs were attributable to alcohol consumption. This represents 0.6% of all DALYs (0.4% of all DALYs for women and 0.8% of all DALYs for men) and 10.9% (12.3% for women and 10.5% for men) of all DALYs attributable to alcohol consumption. See Table 2 for the number of DALYs from liver cirrhosis that are attributable to alcohol consumption, the percentage of all DALYs that were due to alcohol-attributable liver cirrhosis, and the percentage of all alcohol-attributable DALYs due to liver cirrhosis.
      Table 2Alcohol-attributable disability adjusted life years (DALYs) caused by liver cirrhosis in 2010.
      Globally, in 2010 there were 211.1 DALYs per 100,000 people (120.4 DALYs per 100,000 women and 300.3 DALYs per 100,000 men) caused by liver cirrhosis attributable to alcohol consumption. Fig. 3 shows the number of liver cirrhosis DALYs per 100,000 people attributable to alcohol consumption by sex and region. Central Asia experienced the greatest number of alcohol-attributable liver cirrhosis DALYs per 100,000 people for both men and women, with 546.0 DALYs per 100,000 people (435.1 DALYs per 100,000 women, and 655.0 DALYs per 100,000 men). Eastern Europe had the second highest rate of liver cirrhosis DALYs due to alcohol consumption, with 456.1 DALYs per 100,000 people.
      Figure thumbnail gr3
      Fig. 3Alcohol-attributable liver cirrhosis disability adjusted life years (DALYs) per 100,000 people in 2010 by sex and region.
      Unlike deaths, the number of DALYs from liver cirrhosis (corrected for population size) attributable to alcohol consumption was greater among people 35–64 years of age (459.4 DALYs per 100,000 people) when compared to people 15–34 years of age (59.7 DALYs per 100,000 people) and people 65 years of age and older (448.5 DALYs per 100,000 people). The relationship between alcohol-attributable DALYs from liver cirrhosis and age was observed for both men and women. Of all DALYs from liver cirrhosis, 9.7%, 74.1%, and 16.2% occurred in people aged 15–34, 35–64, and 65 years and older, respectively.
      The DALYs due to liver cirrhosis were mainly caused from years of life due to premature mortality rather than due to YLD. Of the burden of DALYs due to alcohol-attributable mortality, 98.5% of the burden was from PYLL and 1.5% of the burden was from YLD. The proportion of PYLL to all DALYs ranged from 97.1% (2.9% from YLD) for the GBD region of East Asia to 99.1% (0.9% from YLD) in the Southeast Asia region. Women had a greater proportion of the alcohol-attributable burden of liver cirrhosis due to YLD (2.4% of DALYs lost) when compared to men (1.1% of DALYs lost). This difference by sex was observed for all regions (see Supplementary data 3 for the percentage of DALYs that were attributable to PYLL and to YLD differentiated by sex and region).
      Of the total burden of liver cirrhosis, 47.9% of liver cirrhosis deaths (46.5% for women and 48.5% for men) and 46.9% of DALYs (44.5% for women and 47.9% for men) were attributable to alcohol consumption. Central Europe had the highest proportion of liver cirrhosis deaths and DALYs attributable to alcohol consumption, with 72.3% of all liver cirrhosis deaths (62.6% for women and 77.1% for men) being attributable to alcohol consumption and 74.6% of all liver cirrhosis DALYs (67.8% for women and 77.4% for men) being attributable to alcohol consumption. North Africa/Middle East had the lowest proportion of liver cirrhosis deaths and DALYs attributable to alcohol consumption, with 14.0% of all liver cirrhosis deaths and 15.9% of all liver cirrhosis DALYs attributable to alcohol consumption.
      The alcohol-attributable liver cirrhosis deaths and DALYs per 100,000 people per litre of alcohol consumed per capita were significantly associated with GDP (PPP). As GDP (PPP) increased by 1,000 USD, the number of alcohol-attributable liver cirrhosis deaths per 100,000 people per litre of alcohol consumed per capita decreased by 0.05 (95% confidence interval (CI): 0.01–0.08) and the number of alcohol-attributable liver cirrhosis DALYs per 100,000 people per litre of alcohol consumed per capita decreased by 1.44 (95% CI: 0.39–2.49). For comparison, in 2010 the world average alcohol-attributable liver cirrhosis deaths per 100,000 people per litre of alcohol consumed per capita was 1.31 and the number of alcohol-attributable liver cirrhosis DALYs per 100,000 people per litre of alcohol consumed per capita was 38.48.

      Global burden of liver cancer

      In 2010, 337,400 deaths (91,500 female deaths and 245,900 male deaths) and 8,670,000 DALYs (2,252,000 DALYs for women and 6,418,000 DALYs for men) from malignant neoplasms were attributable to alcohol consumption. Of these alcohol-attributable malignant neoplasm deaths, 80,600 deaths (14,800 deaths of women and 65,900 deaths of men) were caused by liver cancer and were attributable to alcohol consumption. Liver cancer deaths attributable to alcohol consumption were responsible for 0.2% of all deaths (0.1% of all deaths of women and 0.2% of all deaths of men), 10.7% (6.4% for women and 12.7% for men) of the deaths from liver cancer, 1.7% (0.9% for women and 2.1% for men) of the net number of alcohol-attributable deaths and 23.9% (16.2% for women and 26.8% for men) of all alcohol-attributable cancer deaths. Of the DALYs due to malignant neoplasms attributable to alcohol consumption, 2,142,000 (335,000 DALYs for women and 1,807,000 DALYs for men) were caused by liver cancers attributable to alcohol consumption. This represents 0.1% of all DALYs (0.03% of all DALYs for women and 0.1% of all DALYs for men), 11.2% (6.4% for women and 13.0% for men) of the DALYs from liver cancer, 1.6% (1.0% for women and 1.8% for men) of the net number of alcohol-attributable DALYs lost, and 24.7% (14.9% for women and 28.2% for men) of the DALYs from alcohol-attributable cancers; (see Supplementary data 4 for information on the burden of alcohol-attributable liver cancer).
      Figure thumbnail fx3

      Discussion

      Before discussing the implications of our results, the potential limitations of our research should be addressed. When reading our numbers it should be kept in mind that for both diseases the estimation of alcohol-attributable fractions was made indirectly, by combining distribution of exposure and risk relations. Thus, we avoid the subjectivity of a direct diagnosis for alcoholic liver cirrhosis, but we introduce potential other biases. Each review or summary analysis is only as reliable as the underlying data and since our analyses are dependent on three main sources of data, namely, exposure to alcohol, estimates of the mortality and disease burden, and the risk relations between exposure and outcome, the validity and reliability of these components must be considered. Alcohol consumption consists of recorded and unrecorded consumption data [
      • Rehm J.
      • Rehn N.
      • Room R.
      • Monteiro M.
      • Gmel G.
      • Jernigan D.
      • et al.
      The global distribution of average volume of alcohol consumption and patterns of drinking.
      ,
      • Rehm J.
      • Klotsche J.
      • Patra J.
      Comparative quantification of alcohol exposure as risk factor for global burden of disease.
      ], which, in comparison to other risk exposures, is fairly reliable at the country level [
      • World Health Organization
      Global status report on alcohol and health.
      ,
      • Lim S.S.
      • Vos T.
      • Flaxman A.D.
      • Danaei G.
      • Shibuya K.
      • Adair-Rohani H.
      • et al.
      A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010.
      ,
      • Ezzati M.
      • Lopez A.
      • Rodgers A.
      • Murray C.J.L.
      Comparative quantification of health risks. Global and regional burden of disease attributable to selected major risk factors.
      ], even though the unrecorded consumption data contain more measurement error.
      With respect to risk relations, the analyses contained in this paper are often limited by the use of one-time measurements of exposure when calculating the alcohol-attributable burden of liver cirrhosis and liver cancer. The exclusion of past patterns of drinking is problematic when studying the role of alcohol in the development of long-developing diseases, such as malignant neoplasms, where the time between exposure(s) to a carcinogen and exhibiting symptoms of cancer can range from between 15 and 30 years [
      • Rehm J.
      • Patra J.
      • Popova L.
      Alcohol drinking cessation and its effect on oesophageal and head and neck cancers: a pooled analysis.
      ]. Liver cirrhosis at the individual level is also affected mainly by long-term heavy drinking; however, an immediate decrease in the incidence of liver cirrhosis is seen at the country level, a short time after decreases in alcohol consumption [
      • Zatonski W.
      • Sulkowska U.
      • Manczuk M.
      • Rehm J.
      • Lowenfels A.B.
      • La Vecchia C.
      Liver cirrhosis mortality in Europe, with special attention to central and eastern Europe.
      ,
      • Holmes J.
      • Meier P.S.
      • 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.
      ]. For example, the Gorbachev reforms involving a substantial decrease of alcohol resulted in a marked immediate decrease of liver cirrhosis mortality [
      • Leon D.A.
      • Chenet L.
      • Shkolnikov V.
      • Zakharov S.
      • Shapiro J.
      • Rakhmanova G.
      • et al.
      Huge variation in Russian mortality rates 1984–1994: artefact, alcohol, or what?.
      ]. Similar observations were made in France during the World War II occupation, when alcohol was confiscated [
      • Zatonski W.
      • Sulkowska U.
      • Manczuk M.
      • Rehm J.
      • Lowenfels A.B.
      • La Vecchia C.
      Liver cirrhosis mortality in Europe, with special attention to central and eastern Europe.
      ]. Thus, estimates presented in this paper for 2010 should be accurate as most cases of mortality are triggered by the recent heavy use of alcohol [
      • Holmes J.
      • Meier P.S.
      • 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.
      ].
      Another potential limitation of the methodology used to calculate the alcohol-attributable burden of liver cancer and of liver cirrhosis is the use of adjusted RR functions. The AAF formulas used in our analysis rely on the assumption that the RR functions are unadjusted, and therefore the use of RR functions from meta-analyses (where adjusted RR estimates were used) in our analysis may have introduced an error into our results [
      • Rockhill B.
      • Newman B.
      Use and misuse of population attributable fractions.
      ]. However, this error should have no noticeable effect on the results, since most analyses show no marked differences after adjustment for the usual risk factors tested (see [
      • Rehm J.
      • Baliunas D.
      • Borges G.L.G.
      • Graham K.
      • Irving H.M.
      • Kehoe T.
      • et al.
      The relation between different dimensions of alcohol consumption and burden of disease – an overview.
      ] for an overview of relevant meta-analyses). In addition, if unadjusted RR functions had been used in our analysis, our results would have been more limited. This is because only a small proportion of older studies could have been included if we had used unadjusted RR functions, which would have led to inaccurate estimates of the number of alcohol-attributable deaths. It should be noted that in risk analyses, such as the Comparative Risk Assessment for the GBD studies [
      • Ezzati M.
      • Lopez A.
      • Rodgers A.
      • Murray C.J.L.
      Comparative quantification of health risks. Global and regional burden of disease attributable to selected major risk factors.
      ], almost all of the underlying studies for the different risk factors only report adjusted RR estimates. The need for adjustment to the RR functions may change when other dimensions of alcohol consumption, such as frequency of heavy drinking occasions, are considered.
      The burden of ALDs is huge on a global level. The most direct clinical approach to minimizing the burden of ALD would be timely treatment of its initial, reversible, stages of disease. Given that in early stages ALD is often asymptomatic and can only be identified by laboratory findings [
      • European Association for the Study of the Liver
      EASL clinical practical guidelines: management of alcoholic liver disease.
      ], a focus on screening for alcohol use disorders and their treatment [
      • Room R.
      • Babor T.
      • Rehm J.
      Alcohol and public health: a review.
      ,
      • Agerwala S.M.
      • McCance-Katz E.F.
      Integrating screening, brief intervention, and referral to treatment (SBIRT) into clinical practice settings: a brief review.
      ] seems to be the most feasible approach for prevention of ALD. At the same time, given that alcohol use disorders are very likely to be accompanied by at least a mild form of ALD, clinicians should approach treatment of alcohol use disorders with the prevention and potential treatment of ALD in mind. Thus, treatment should include psychosocial and pharmacotherapies – treatment of alcohol use disorders, treatment of alcohol liver disease, correction of nutritional status, etc. Prescription of the most widely used pharmacotherapies for alcohol use disorders, i.e., disulfiram, naltrexone and acamprosate, should be considered after assessment of ALD, and in cases of advanced ALD preference should be given to medications that are not hepatotoxic [
      • European Association for the Study of the Liver
      EASL clinical practical guidelines: management of alcoholic liver disease.
      ].
      In principle, all burden associated with ALD is avoidable [
      • Rehm J.
      • Taylor B.
      • Patra J.
      • Gmel G.
      Avoidable burden of disease: conceptual and methodological issues in substance abuse epidemiology.
      ], but prevention is difficult as it attempts to change culturally engrained habits such as heavy alcohol consumption. To combat this burden, the World Health Organization has recently launched a global strategy to reduce the harmful use of alcohol [
      • World Health Organization
      Global strategy to reduce the harmful use of alcohol.
      ], building on earlier recommendations [
      • Babor T.
      • Caetano R.
      • Casswell S.
      • Edwards G.
      • Giesbrecht N.
      • Graham K.
      • et al.
      Alcohol: no ordinary commodity. Research and public policy.
      ,
      • Anderson P.
      • Chisholm D.
      • Fuhr D.
      Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol.
      ]. This global strategy focuses on ten key areas of policy options and interventions at the national level and four priority areas for global action. The ten areas for national action include health services’ response and community action, but focus on preventive public health actions such as drink-driving policies and countermeasures; reductions of availability of alcohol; ban of marketing of alcoholic beverages; and increase of prices (i.e., via taxation). It also includes harm reduction measures to reduce the negative consequences of drinking and alcohol intoxication of those who drink. Other foci refer to a reduction of unrecorded illicit and informally produced alcohol, and the establishment of a monitoring and surveillance system [
      • World Health Organization
      Global strategy to reduce the harmful use of alcohol.
      ].
      Most of these measures are not only effective but also cost-effective, with taxation increases to increase the price of alcoholic beverages, reductions of availability of alcohol, and bans of its marketing being identified as “best buys” for the reduction of alcohol-attributable harm [
      • Anderson P.
      • Chisholm D.
      • Fuhr D.
      Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol.
      ,
      • Chisholm D.
      • Rehm J.
      • van Ommeren M.
      • Monteiro M.
      Reducing the global burden of hazardous alcohol use: a comparative cost-effectiveness analysis.
      ,
      • World Health Organization
      Global status report on noncommunicable diseases 2010. Description of the global burden of NCDs, their risk factors and determinants.
      ].
      The global burden of ALDs strongly reinforces the necessity of implementing such public health strategies to prevent alcohol-attributable harm, even though to do so may not always be the most popular with politicians who tend to focus on education or individual-based responses [
      • Room R.
      • Babor T.
      • Rehm J.
      Alcohol and public health: a review.
      ,
      • Rehm J.
      • Babor T.
      • Room R.
      Education, persuasion and the reduction of alcohol-related harm: a reply to Craplet.
      ].

      Financial support

      The present article was supported by salary and infrastructure support from the Ontario Ministry of Health and Long-Term Care to the first author. Kevin Shield received funds from the University of Toronto Open Fellowship Award and the Canadian Institutes of Health Frederick Banting and Charles Best Canada Graduate Scholarship .

      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.

      Appendix A. Supplementary data

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