The Global Impact of Alcohol Consumption on Premature Mortality and Health in 2016

This study aimed to estimate the impact of alcohol use on mortality and health among people 69 years of age and younger in 2016. A comparative risk assessment approach was utilized, with population-attributable fractions being estimated by combining alcohol use data from the Global Information System on Alcohol and Health with corresponding relative risk estimates from meta-analyses. The mortality and health data were obtained from the Global Health Observatory. Among people 69 years of age and younger in 2016, 2.0 million deaths and 117.2 million Disability Adjusted Life Years (DALYs) lost were attributable to alcohol consumption, representing 7.1% and 5.5% of all deaths and DALYs lost in that year, respectively. The leading causes of the burden of alcohol-attributable deaths were cirrhosis of the liver (457,000 deaths), road injuries (338,000 deaths), and tuberculosis (190,000 deaths). The numbers of premature deaths per 100,000 people were highest in Eastern Europe (155.8 deaths per 100,000), Central Europe (52.3 deaths per 100,000 people), and Western sub-Saharan Africa (48.7 deaths per 100,000). A large portion of the burden of disease caused by alcohol among people 69 years of age and younger is preventable through the implementation of cost-effective alcohol policies such as increases in taxation.


Introduction
Alcohol consumption is a leading risk factor for premature mortality and the burden of disease worldwide. Research in developed and developing countries has found that individuals of younger ages are disproportionately affected by alcohol [1][2][3]. For instance, alcohol is estimated to be the leading risk factor for the burden of disease among people 15 to 49 years of age, followed by high body mass index, high blood pressure, and dietary risks [3]. This population also has a large proportion of their expected lifespans remaining, contributes relatively more to the economy, and plays important roles in caring for their families [4].
In response to the burden of disease caused by alcohol, the World Health Organization (WHO), through its Global strategy to reduce the harmful use of alcohol and its Global

Materials and Methods
A comparative risk assessment methodology was utilized to estimate the burden of disease attributable to alcohol use in 2016. These estimations were based on the theoretical minimum risk exposure level (TMREL) of lifetime abstention. Lifetime abstention was utilized as a TMREL based on historical precedent, and the observation that lifetime abstainers may have the lowest risk of overall health loss [10]. The population-attributable fraction (PAF) for alcohol use was estimated based on a Levin-based method which combines data on alcohol exposure with corresponding relative risk (RR) estimates [11,12]. Information regarding the methods utilized and the data sources can be found in the Supplemental Material and in the paper by Shield et al. [1].

Relative Risk Estimates
Alcohol RR estimates for chronic disease outcomes (except from ischemic diseases) were obtained from meta-analyses and based on average drinking (in grams per day) [13]. The lag time between alcohol use and disease occurrence was only modelled for cancer (based on the estimate that there is a 10 year period between exposure and disease outcomes [14]). Heavy episodic drinking (HED) was utilized in the modelling for the RRs for ischemic diseases and injuries [1]. All RR estimates were reviewed and approved by the WHO Technical Advisory Group on Alcohol and Drug Epidemiology. The sources of RR estimates are outlined in Supplemental Material Table S1.

Mortality, Morbidity, and Population Data
Data on mortality, Years of Life Lost (YLL), morbidity measured using Years Lived with Disability (YLD), age, sex, country, year, and by cause of mortality and/or morbidity were obtained from the WHO's Global Health Estimates [15]. The total burden of disease was measured using Disability Adjusted Life Years (DALYs) lost. Estimates of premature mortality were based on a cut off of deaths which occurred among people 69 years of age and younger [4,16].
Alcoholic cardiomyopathy deaths, YLL, and YLD were estimated using the methods of Manthey and colleagues [17] as they were not directly estimated in the WHO's Global Health Estimates. The WHO's road traffic death database [18] was used to determine the fractions of alcohol-attributable motor vehicle deaths which involved a driver and those traffic deaths which involved people other than the driver.
Population data by age, sex, country, and year were obtained from the UN Population Division [19]. Deaths, YLLs, YLDs, and DALYs lost were aggregated into five-year age groups, beginning at 0 years until 84 years, followed by the category of 85 years and older; alcohol PAFs were applied to these age groupings.
Data were aggregated by GBD region (see: http://ghdx.healthdata.org (accessed on 1 January 2021) for regional groupings) and by Human Development Index (HDI) region Nutrients 2021, 13, 3145 3 of 13 (see Figure S1 in the Supplementary Materials for HDI groupings). HDI categories were obtained from the United Nations Development Programme [20]. The HDI is based on having a long and healthy life (i.e., life expectancy at birth), being knowledgeable (i.e., expected years of schooling and mean years of schooling for adults 25 years of age and older), and having a decent standard of living (i.e., Gross National Income per capita) [20].
The 95% uncertainty intervals (see Tables S2-S14 in Supplementary Materials) were based on a set of 1000 simulations of all lowest level parameters (i.e., parameters sampled from their respective error distributions). These parameters were then used to estimate 1000 simulated estimates of the alcohol-attributable burden of disease. From these simulations, the 2.5th and 97.5th percentiles were utilized for the 95% uncertainty intervals.
Analyses were performed using the statistical software package R [21].

Results
In 2016, there were 2.0 million premature deaths and 117.2 million DALYs lost globally due to alcohol use, representing 7.1% of all premature deaths and 5.5% of all DALYs lost in that year (see Tables 1 and 2). In contrast, 3.2% of all deaths and 3.0% of all DALYs lost among people 70 years of age and older were attributable to alcohol consumption. An estimated 70.7% of all alcohol-attributable deaths and 89.2% of all alcohol-attributable DALYs lost globally in 2016 were premature, i.e., among those 69 years of age and younger. In comparison, 52.0% of all deaths and 81.8% of all DALYs lost globally in 2016 were premature. The alcohol-attributable deaths and DALYs lost among those 69 years of age and younger were greater among men (1.6 million deaths and 90.9 million DALYs lost) compared to women (0.5 million deaths and 26.3 million DALYs lost). The largest proportion of premature deaths that were attributable to alcohol occurred among people 30-39 years of age (13.3%) and 20-29 years of age (13.0%). See Tables S2 to S17 for data on sex-specific alcohol-attributable deaths, YLL, YLD, and DALYs lost.
The leading causes of the burden of premature alcohol-attributable deaths were cirrhosis of the liver (457,000 deaths), road injuries (338,000 deaths), and tuberculosis (190,000 deaths) (see Figure 1). Road injuries and cirrhosis of the liver were the leading causes of alcohol-attributable deaths among those aged 0 to 39 and 40 to 69 years of age, respectively. The proportion of alcohol-attributable deaths due to road injuries decreased with age from 100% of all alcohol-attributable deaths among those aged 0-14 years to 7.0% among those aged 60-69 years. The proportion of alcohol-attributable deaths due to cirrhosis of the liver increased with age, peaking at 26.4% of all alcohol-attributable deaths among those 50-59 years of age. The proportion of alcohol-attributable deaths due to tuberculosis increased with age, peaking at 10.7% of all alcohol-attributable deaths among those 40-49 years of age.  respectively. The proportion of alcohol-attributable deaths due to road injuries decre with age from 100% of all alcohol-attributable deaths among those aged 0-14 years to among those aged 60-69 years. The proportion of alcohol-attributable deaths due to rhosis of the liver increased with age, peaking at 26.4% of all alcohol-attributable de among those 50-59 years of age. The proportion of alcohol-attributable deaths due t berculosis increased with age, peaking at 10.7% of all alcohol-attributable deaths am those 40-49 years of age.

Alcohol-Attributable Burden of Disease by Region
The numbers of premature alcohol-attributable deaths and DALYs lost per 100 people showed large variations globally (see Figures 2 and 3). The numbers of prema alcohol-attributable deaths were highest in Eastern Europe (155.8 deaths per 100, Central Europe (52.3 deaths per 100,000 people), and Western sub-Saharan Africa deaths per 100,000). In 2016, the two leading contributors to alcohol-attributable de among all regions were either cirrhosis of the liver or road injuries, except for thre gions: Asia Pacific with self-harm, Southern sub-Saharan Africa with tuberculosis, Eastern Europe with ischaemic heart disease being the largest contributors, respect (see Figure 3). The second largest contributors to alcohol-attributable deaths in Sout  Figure 1. Alcohol-attributable deaths and disability adjusted life years (DALYs) lost by age.

Alcohol-Attributable Burden of Disease by Region
The numbers of premature alcohol-attributable deaths and DALYs lost per 100,000 people showed large variations globally (see Figures 2 and 3). The numbers of premature alcohol-attributable deaths were highest in Eastern Europe (155.8 deaths per 100,000), Central Europe (52.3 deaths per 100,000 people), and Western sub-Saharan Africa (48.7 deaths per 100,000). In 2016, the two leading contributors to alcohol-attributable deaths among all regions were either cirrhosis of the liver or road injuries, except for three regions: Asia Pacific with self-harm, Southern sub-Saharan Africa with tuberculosis, and Eastern Europe with ischaemic heart disease being the largest contributors, respectively (see Figure 3). The second largest contributors to alcohol-attributable deaths in Southern sub-Saharan Africa and Eastern Europe were HIV/AIDS and alcohol use disorders, respectively. Figure S2 outlines the burden of alcohol-attributable premature YLL and YLD globally. Figure S3 outlines the burden of alcohol-attributable premature YLL and YLD by GBD region. sub-Saharan Africa and Eastern Europe were HIV/AIDS and alcohol use disorders, respectively. Figure S2 outlines the burden of alcohol-attributable premature YLL and YLD globally. Figure S3 outlines the burden of alcohol-attributable premature YLL and YLD by GBD region.

Alcohol-Attributable Burden of Disease by Human Development Index
The burden of premature alcohol-attributable deaths and DALYs lost varied by HDI region (see Figure 4). The number of alcohol-attributable deaths was highest in countries with a very high HDI (43.3 deaths and 2339.9 DALYs lost per 100,000), followed by low HDI countries (33.7 deaths and 1966.1 DALYs lost per 100,000), high HDI countries (26.8 deaths and 1502.3 DALYs lost per 100,000) and medium HDI countries (24.8 deaths and 1392.5 DALYs lost per 100,000). The leading cause of death was cirrhosis of the liver in very high HDI countries (8.2 deaths per 100,000), low HDI countries (7.4 deaths per 100,000), and medium HDI countries (6.6 deaths per 1,000,000), and was road injuries in high HDI countries (5.9 deaths per 100,000). For DALYs lost, the leading contributor to the premature alcohol-attributable burden of disease was alcohol use disorders for very-high HDI countries (449.3 DALYs lost per 100,000), liver cirrhosis for medium HDI countries (297.3 DALYs lost per 100,000 people), and road injuries for low HDI countries (431.2 DALYs lost per 100,000 people) and high HDI countries (354.4 DALYs lost per 100,000). Figure S4 outlines the burden of premature YLL and YLD by HDI region.

Alcohol-Attributable Burden of Disease by Human Development Index
The burden of premature alcohol-attributable deaths and DALYs lost varied by HDI region (see Figure 4). The number of alcohol-attributable deaths was highest in countries with a very high HDI (43.3 deaths and 2339.9 DALYs lost per 100,000), followed by low HDI countries (33.7 deaths and 1966.1 DALYs lost per 100,000), high HDI countries (26.8 deaths and 1502.3 DALYs lost per 100,000) and medium HDI countries (24.8 deaths and 1392.5 DALYs lost per 100,000). The leading cause of death was cirrhosis of the liver in very high HDI countries (8.2 deaths per 100,000), low HDI countries (7.4 deaths per 100,000), and medium HDI countries (6.6 deaths per 1000,000), and was road injuries in high HDI countries (5.9 deaths per 100,000). For DALYs lost, the leading contributor to the premature alcohol-attributable burden of disease was alcohol use disorders for veryhigh HDI countries (449.3 DALYs lost per 100,000), liver cirrhosis for medium HDI countries (297.3 DALYs lost per 100,000 people), and road injuries for low HDI countries (431.2 DALYs lost per 100,000 people) and high HDI countries (354.4 DALYs lost per 100,000). Figure S4 outlines the burden of premature YLL and YLD by HDI region.

Discussion
The results of this study indicate that alcohol-attributable deaths and health loss occurred among people relatively young in age. The proportions of alcohol-attributable deaths and DALYs lost that were premature were greater than the proportions of all-cause deaths and DALYs lost that were considered premature. This indicates that alcohol use disproportionately affects the health of people who are younger in age. The cause composition of the premature alcohol-attributable burden is unique when compared to the burden among people 70 years of age and older, with cirrhosis of the liver, road injuries, and tuberculosis being the primary contributors to this burden. Furthermore, regional and societal development-based variations in the magnitude of the premature alcohol-attributable burden of disease and the cause composition of this burden were observed.
This study modelled both the detrimental and protective effects of alcohol consumption on health. Specifically, alcohol consumed at low amounts, and not on HED occasions has a protective effect on diabetes, ischemic heart disease, and ischemic stroke [13]. This

Discussion
The results of this study indicate that alcohol-attributable deaths and health loss occurred among people relatively young in age. The proportions of alcohol-attributable deaths and DALYs lost that were premature were greater than the proportions of allcause deaths and DALYs lost that were considered premature. This indicates that alcohol use disproportionately affects the health of people who are younger in age. The cause composition of the premature alcohol-attributable burden is unique when compared to the burden among people 70 years of age and older, with cirrhosis of the liver, road injuries, and tuberculosis being the primary contributors to this burden. Furthermore, regional and societal development-based variations in the magnitude of the premature alcohol-attributable burden of disease and the cause composition of this burden were observed.
This study modelled both the detrimental and protective effects of alcohol consumption on health. Specifically, alcohol consumed at low amounts, and not on HED occasions has a protective effect on diabetes, ischemic heart disease, and ischemic stroke [13]. This study found that for the premature disease burden, the detrimental effects of alcohol at the population level outweighed the protective effects. At the individual level, the net effect of alcohol consumption on overall health is unknown; however, a recent modelling study found no level of alcohol consumption that provided a net health benefit [10].
The premature burden of disease attributable to alcohol consumption was characterized by tuberculosis, liver cirrhosis, and injuries. Liver cirrhosis is mainly linked to the overall volume of drinking, while injuries attributable to alcohol are mostly related to intoxication (i.e., binge alcohol consumption) [13]. Tuberculosis risk (i.e., the impact of alcohol on the immune system) is related both to the overall volume of alcohol consumed and binge drinking; however, due to the lack of studies, the impact of alcohol use on tuberculosis was modelled based only on the overall volume of alcohol consumed [13]. Therefore, both overall volume of alcohol consumed and drinking to intoxication are factors leading to the premature burden of disease attributable to alcohol consumption.
Tuberculosis remains an enormous public health concern globally, especially in low and medium HDI countries [22]. The treatment of tuberculosis and the interaction between HIV/AIDS and tuberculosis are key public health priorities [23]. Alcohol use is a key risk factor for both diseases (Morojele et al., this issue), which if addressed can substantially reduce the health burden of tuberculosis and HIV/AIDS. The burden of disease due to liver cirrhosis was high in all HDI categories and in most GBD regions. The burden of alcoholic liver cirrhosis is affected by multiple risk factors which interact with alcohol, including hepatitis B and C infections, obesity, and socio-economic status [24]. The burden of alcoholrelated injuries is problematic as investment in preventing mortality from injury has fallen behind other causes of death, such as HIV/AIDS and reproductive health [21]. Furthermore, mental health concerns have been overlooked in terms of public health programming, especially in young people [10] where injuries and neuropsychiatric conditions are greatly impacted by alcohol consumption [22].
The burden of premature disease attributable to alcohol consumption was highest in Eastern Europe, Central Europe, and Western sub-Saharan Africa. The Central and Eastern Europe region have a high overall volume of alcohol consumption and a high prevalence of HED [5,6]. Alcohol control policy measures, including increases in alcohol prices and decreases in availability, have been implemented in the Eastern Europe region and have resulted in marked downward shifts in mortality and the burden of disease [25]. The Western sub-Saharan Africa region has a relatively low overall volume of alcohol consumption. The burden of alcohol-attributable premature disease in this region was driven mainly by infectious diseases, liver cirrhosis, and injuries. Cirrhosis-related deaths doubled in the sub-Saharan Africa region between 1980 and 2010, with hepatitis B virus, hepatitis C virus, and alcohol use being contributing factors to this increase [26]. Furthermore, treatment of liver cirrhosis is unavailable in most parts of sub-Saharan Africa, due to a shortage of hepatologists and gastroenterologists, interventional radiologists, hepatobiliary surgeons, and pathologists [27].

Limitations
The methods used in this paper are limited by several factors. Firstly, estimates of alcohol consumption came from surveys which are susceptible to numerous biases which lead to an underestimation of alcohol use. Per capita consumption of alcohol is utilized to estimate the volume of alcohol use among drinkers to avoid bias; however, no correction exists for the prevalence of HED. This study did not fully account for the interaction between alcohol use and other risk factors, such as smoking (increased risk of cancer [28]), hepatitis B and C (increased risk of liver cirrhosis [29]), and obesity (increased risk of liver cirrhosis [24,30]). Furthermore, the study did not account for the differential alcohol RRs by socio-economic status. Furthermore, although depression has been shown to be causally related to alcohol consumption, it was not included in the estimates of the alcohol-attributable burden of disease due to depression also causally increasing alcohol consumption [13].
This study is also limited as deaths and health loss due to interpersonal harm are based on the alcohol consumption of the person who experiences the harm and not the alcohol consumption of the person who inflicts the harm. This is due to the relative risks of injuries from assault being based on the person who experiences the harm and not the person who is inflicting the harm [13]. Therefore, estimates of intentional harm are likely underestimated for children and women who are often victims of alcohol-related violence [31]. It is important to note that violence against women and children is a major public health, social policy, and human rights concern that spans disciplines and geographical boundaries [32][33][34][35]. Globally, domestic violence is one of the largest sources of non-fatal injuries to women and children [36], resulting in avoidable inequities in health status, and increases in the risk of mental health and physical conditions [37].

Health Policies
The health harms and inequities outlined in the paper should be considered in the context of population-level interventions which can reduce the alcohol-attributable burden of disease and are sustainable, scalable, and politically, economically, and technically feasible [38]. Several alcohol interventions have been designated as "best buys" by the WHO as they are more cost-effective than most other interventions designed for other risk factors [39]. These include increases in taxation and restrictions on availability and marketing. Other policies include WHO cost-effective "very good buys," such as enactment and enforcement of impaired-driving laws and blood-alcohol-concentration limits [39,40].
The need to intervene to reduce the burden of premature health loss attributable to alcohol consumption can be viewed under the framework of utilitarian ageism. The framework of utilitarian ageism, which is often observed in medical practice, states that there should be prioritization of treatments and interventions for health loss among the young (as the old have lived longer) [41,42].
Despite the majority of the burden of disease attributable to alcohol consumption occurring among people 0 to 69 years of age, alcohol leads to a substantial burden of disease among people 70 years of age and older. Interventions such as the WHO best buys and very best buys should also be prioritized to reduce the burden among people 70 years of age and older. Furthermore, these policies should apply equally to beer, wine, spirits, and other alcoholic beverages as the harm caused by alcohol is based on ethanol content regardless of whether the ethanol is consumed in the form of beer, wine, or spirits (with the exception of alcohol poisonings which are caused predominately by the consumption of spirits) [13].

Conclusions
Alcohol consumption remains a leading risk factor for the burden of disease, especially among people younger in age. Given the high global alcohol-attributable burden of disease, the development and implementation of cost-effective alcohol control policies can further reduce in the near future the social, economic, and health burdens resulting from the use of alcohol.

Funding: This research was funded by the World Health Organization.
Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.
Data Availability Statement: All statistical code (i.e., R code) and input files used to produce the results presented in this paper are available to the general public. To obtain the code and input files, please contact the author, Kevin Shield (Kevin.Shield@camh.ca).