Graphical Abstract
INTRODUCTION
In 2021, alcohol consumption ranked as the ninth leading cause of the global disease burden [1]. Alcohol use has been causally linked to numerous disease and injury categories, with over 200 of the International Classification of Diseases, 10th Revision (ICD-10) three-digit categories being attributable to alcohol [2-4]. In particular, alcohol use disorder (AUD) constitutes a chronic brain disease characterized, among many other features, by compulsive heavy alcohol use and loss of control over alcohol intake, leading to significant psychological, social, and physical harm [5]. AUD is a highly prevalent mental health disorder, affecting around 3.7% of the global adult population in 2019 [6]. Furthermore, alcohol-related liver disease (ALD) is a striking health consequence, with higher mortality in individuals with cirrhosis [7]. The economic costs due to alcohol use were estimated at 2.6% of global gross domestic product, most of them attributable to losses in productivity (61.2%) [8]. In the United States of America (USA), the annual direct and indirect costs of ALD are projected to increase from $31 billion in 2022 to $66 billion in 2040, representing a 118% increase in this period [9].
Individuals with ALD have two diseases to treat (AUD and chronic liver disease) [10,11], and ideal treatments should be multidisciplinary to manage and treat both comorbid conditions [12]. Unfortunately, timely access to AUD treatments for individuals with ALD is scarce, even in developed countries, due to several barriers at the patient, clinician, and organizational levels [13]. For example, a retrospective study conducted in the USA, including 35,682 veterans with ALD, demonstrated that 12% received behavioral therapy after AUD diagnosis, and 1% received behavioral therapy with pharmacotherapeutic agents [14]. Also, difficulties in hepatocellular carcinoma (HCC) surveillance have been identified in ALD. In the USA and Europe, fewer than 30% of HCC cases are diagnosed by surveillance in patients with cirrhosis, and screening among individuals with ALD is less commonly performed than in those with hepatitis C virus-related cirrhosis [15]. Thus, gaps in both healthcare access and treatment likely contribute to the burden of disease due to alcohol.
While numerous studies have examined the local and regional epidemiology of ALD and AUD, there are significant gaps in understanding their global epidemiology [16,17]. The Coronavirus Disease 2019 (COVID-19) pandemic has further deepened this understanding through its significant effects on disease burden, high mortality rates, long-term health impacts, and disruptions to healthcare systems, which have undoubtedly influenced the burdens of ALD, AUD, and liver cancer [18]. To bridge these gaps, we leveraged the Global Burden of Disease (GBD) Study 2021 data, one of the most comprehensive and up-to-date global datasets for ALD, AUD, liver cancer, and their risk factors available [18-20]. Our study aimed to investigate the temporal trends of ALD, AUD, and alcohol-attributable primary liver cancer across 204 countries and territories, stratifying the data by sex, geographic location, and sociodemographic index (SDI) from 2000 to 2021.
MATERIALS AND METHODS
Data source
The study accessed data on AUD, ALD, and alcohol-attributable liver cancer incidence, prevalence, and deaths from 2000 to 2021 using data from the GBD 2021 [18-20]. The data stratified by sex, region, and country were accessed through the Global Health Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool), a resource maintained by the Institute for Health Metrics and Evaluation (University of Washington, USA) [18-20].
This study involves human participants, but an Ethics Committee(s) or Institutional Board(s) exempted this study by the Institute For Health Metrics and Evaluation in 2021. The data utilized in this article were obtained from the publicly available GBD database and, thus, did not necessitate any institutional review board approval, ethics clearance, or consent from study subjects.
Estimation methods
The estimation methods for the GBD 2021 and the methodology for estimating the burden of diseases were described in previous GBD study publications [18-20]. For AUD, the analysis utilized ICD-10 codes E24.4, F10-F10.9, G31.2, G62.1, G72.1, P04.3, Q86.0, R78.0, and X45-X45.9, X65-X65.9, Y15-Y15.9. For ALD and alcohol-attributable primary liver cancer, estimates of etiologies for chronic liver disease (ICD10: B18-B18.9, I85-I85.9, I98.2, K70-K70.3, K71.7, K73-K75, K75.2, K75.4-K76.2, K76.4-K76.9, and K77.8) and liver cancer (C22-C22.8, D13.4) were derived from a systematic GBD literature search, incorporating population-based studies. Data for five etiologies—chronic hepatitis B virus infection, chronic hepatitis C virus infection, ALD, metabolic dysfunction associated steatohepatitis. The proportions for each etiology were scaled to sum to 100%, and the ALD and alcohol-attributable primary liver cancer were extracted. In summary, data were obtained from various reliable sources, including population-based cancer registries, vital registration systems, and verbal autopsy studies (Supplementary materials). Several statistical methods were employed to enhance the consistency and reliability of the data, including misclassification correction, garbage code redistribution, and noise reduction algorithms. These techniques minimize biases to improve the accuracy of estimates. The study employed a Cause-of-death Ensemble model, a Bayesian geospatial regression analysis [18-20], that calculates mortality by age, sex, geographical location, and year.
Countries were grouped by development level using the SDI (i.e., low, low-middle, middle, high-middle, high), a composite measure of lag-distributed income per capita, average years of education, and fertility rates among females younger than 25 years (Supplementary Table 1) [1]. The burden of diseases was stratified into 21 regions based on the GBD region classification, which are Central Asia, Central Europe, Eastern Europe, Australasia, High-income Asia-Pacific, High-income North America, Southern Latin America, Western Europe, Andean Latin America, Central Latin America, Tropical Latin America, Caribbean, North Africa and Middle East, South Asia, East Asia, Southeast Asia, Oceania, Central Sub-Saharan Africa, Eastern Sub-Saharan Africa, Southern Sub-Saharan Africa, and Western Sub-Saharan Africa [21].
Statistical analysis
The study reports an estimate for the estimates of prevalence, incidence, and deaths accompanied by 95% uncertainty intervals (UIs). These intervals are determined by identifying the 2.5th and 97.5th ranked values across all 1,000 draws from the posterior distribution. This approach provides a range of values that reflects the uncertainty inherent in statistical modeling. The change in any variable between 2000 and 2021 was calculated as follows: ([value in 2021–value in 2000]/value in 2000). Age-standardized rates (ASRs), including age-standardized prevalence rate (ASPR), age-standardized incidence rate (ASIR), and age-standardized death rate (ASDR) per 100,000 were calculated using the GBD population estimate method [22]. ASRs provide several advantages, including adjusting for age distribution differences to allow fair comparisons across regions, countries, or time periods. Unlike crude numbers, ASRs per 100,000 standardize data by population size, facilitating comparisons between countries with varying populations or prevalence rates. This ensures that observed differences represent actual disease burden rather than demographic variations. To assess changes in ASRs over time, the study calculated the annual percent change (APC) and its 95% confidence interval (CI). When both the annualized rate of change and the lower boundary of its 95% CI were positive, it was classified as an increasing trend. Conversely, if the annualized rate of change and the upper boundary of its 95% CI were negative, it was classified as a decreasing trend. This analysis used the Joinpoint regression program, version 4.9.1.0 (https://surveillance.cancer.gov/joinpoint), developed by the Statistical Research and Applications Branch of the National Cancer Institute in Bethesda.
RESULTS
The global burden of alcohol use disorder, alcohol-related liver disease, and alcohol-attributable primary liver cancer
In 2021, there were 111.12 million cases of AUD (+14.66% from 2000), 3.02 million cases of ALD (+38.68% from 2000), and 132,030 cases of alcohol-attributable primary liver cancer (+94.12% from 2000) (Tables 1–3, Fig. 1A–C). In terms of incidence, there were 55.78 million new cases of AUD (+15.24% from 2000), 462,690 cases of ALD (+38.29% from 2000), and 99,540 cases of alcohol-attributable liver cancer (+82.89% from 2000) (Tables 1–3). There were 158,470 deaths from AUD (-3.23% from 2000), 354,250 deaths from ALD (+32.60% from 2000), and 92,230 deaths from alcohol-attributable primary liver cancer (+76.75% from 2000) (Tables 1–3, Fig. 1D–F). The ASPRs of AUD, ALD, and primary liver cancer from alcohol were 1,335.43 (95% UI 1,153.65 to 1,539.75), 34.81 (95% UI 28.88 to 40.26), and 1.51 (95% UI 1.23 to 1.82), respectively (Tables 1–3, Fig. 1A–C). The ASIRs of these conditions were 673.98 (95% UI 563.13 to 776.68), 5.34 (95% UI 4.40 to 6.25), and 1.14 (95% UI 0.93 to 1.38), respectively (Tables 1–3). The ASDRs were 1.84 (95% UI 1.50 to 2.01), 4.08 (95% UI 3.45 to 4.81), and 1.06 (95% UI 0.86 to 1.29) for AUD, ALD, and alcohol-attributable primary liver cancer, respectively (Tables 1–3, Fig. 1D–F). An examination of trends from 2000 to 2021 indicated an annual rise in the ASPR for alcohol-attributable primary liver cancer (APC: 0.59%, 95% CI 0.52 to 0.67%), whereas decrease in AUD (APC: -0.90%, 95% CI –0.94 to –0.86%) and ALD (APC –0.71%; 95% CI –0.75 to –0.67%) (Tables 1–3). Similarly, the trend of ASIR increased from alcohol-attributable primary liver cancer (APC 0.26%; 95% CI 0.22 to 0.30%), yet decreased in AUD (APC –0.78%; 95% CI –0.81 to –0.75%) and ALD (APC –0.84%; 95% CI –0.87 to –0.82%) (Tables 1–3). ASDRs remained stable in alcohol-attributable primary liver cancer but declined in AUD (APC –2.19%; 95% CI –2.44 to –1.93%) and ALD (APC –1.11%; 95% CI –1.19 to –1.04%) (Tables 1–3).
Regarding sex, changes from 2000 to 2021 from ALD and AUD were less pronounced in females than males (Supplementary Fig. 1A–C). When analyzed during the pandemic timeframe (2019 to 2021) versus the pre-pandemic timeframe (2000 to 2019), prevalence, incidence, and mortality (except for AUD) underwent nearly equal or higher degrees of changes in the pre-pandemic compared to the pandemic timeframe (Supplementary Fig. 1A–F). From 2019 to 2021, AUD prevalence and incidence increased in males, whereas it decreased in females (Supplementary Fig. 1D–E). AUD death decreased at a higher degree in females than males (Supplementary Fig. 1F). However, ALD metrics increased more in females: prevalence by 4.90%, incidence by 4.96%, and mortality by 1.07%. In males, prevalence increased by 3.87%, incidence by 3.73%, and mortality by 0.88% (Supplementary Fig. 1D–F).
Alcohol use disorder
The highest burden of AUD was observed in Eastern Europe, where the ASPR, ASIR, and ASDR were 3,292.73 (95% UI 2,901.33 to 3,724.07), 1,634.85 (95% UI 1,373.51 to 1,906.75), and 10.66 (95% UI 9.82 to 11.56), respectively (Table 1). While a decline in ASPR was observed across most regions, ASPR was increased in Australasia (APC 0.72%; 95% CI 0.59 to 0.84%), Oceania (APC 0.13%; 95% CI 0.11 to 0.15%), and Western Sub-Saharan Africa (APC 0.08%; 95% CI 0.05 to 0.11%) (Table 1). Considering ASIR, most regions exhibited a decrease, but increased in Australasia (APC 0.76%; 95% CI 0.65 to 0.86%), Oceania (APC 0.12%; 95% CI 0.10 to 0.14%), and Western Sub-Saharan Africa (APC 0.10%; 95% CI 0.07 to 0.12%) (Table 1). On the other hand, ASDR increased only in High-income North America (APC 1.83%; 95% CI 1.16 to 2.50%) (Table 1).
When evaluated against the SDI, high SDI countries exhibited the highest burden of AUD with ASPR, ASIR, and ASDR of 1,847.63 (95% UI 1,603.23 to 2,115.44), 915.37 (95% UI 772.84 to 1,052.98), and 2.58 (95% UI 2.50 to 2.66), respectively (Table 1, Fig. 2A, B). ASDR decreased in all SDI strata except remained stable in high SDI countries (Table 1).
The national difference in ASPRs of AUD among different nations in 2021 is illustrated in Figure 3A, Supplementary Table 2. Briefly, the ASPR of AUD was highest in Mongolia with an ASPR of 4,716.94 (95% UI 3,986.35 to 5,453.81), followed by Guatemala at 4,049.97 (95% UI 3,444.01 to 4,623.66), El Salvador at 3,917.28 (95% UI 3,312.16 to 4,461.73), and Kazakhstan at 3,895.96 (95% UI 3,302.65 to 4,889.17). Around 40 countries/ territories showed an uptrend of ASPR from AUD. New Zealand (APC 3.46%; 95% CI 3.21 to 3.70%), Mongolia (APC 1.49%; 95% CI 1.30 to 1.67%), Taiwan (APC 1.24%; 95% CI 0.95 to 1.52%), and Uruguay (APC 0.64%; 95% CI 0.56 to 0.72%) exhibited the highest increases of ASPR from 2000 to 2021 (Supplementary Table 2).
Alcohol-related liver disease
In 2021, the highest ASPR of ALD was observed in Eastern Europe, with an ASPR of 125.22 (95% UI 102.77 to 148.78). In contrast, ASIR and ASDR were highest in Central Asia, with 18.56 (95% UI 14.78 to 22.14) and 11.63 (95% UI 9.26 to 14.28), respectively (Table 2). The ASPR, ASIR, and ASDR of ALD demonstrated a downward trend in most GBD regions from 2000 to 2021 (Table 2). However, Central Asia (APC 0.88%; 95% CI 0.79 to 0.97%), Eastern Europe (APC 0.68%; 95% CI 0.53 to 0.82%), Central Sub-Saharan Africa (APC 0.16%; 95% CI 0.14 to 0.18%), and South Asia (APC 0.10%; 95% CI 0.08 to 0.13%) exhibited an uptrend in ASPR. ASIR increased in Eastern Europe (APC 0.47%; 95% CI 0.35 to 0.59%) and Central Asia (APC 0.44%; 95% CI 0.32 to 0.56%) (Table 2). ASDR increased in Eastern Europe (APC 0.99%; 95% CI 0.58 to 1.41%) and High-income North America (APC 0.74%; 95% CI 0.38 to 1.10%) (Table 2).
Regarding SDI, high SDI countries exhibited the highest ASPR with a value of 39.37 (95% UI 32.74 to 45.26), whereas low SDI countries exhibited the highest ASIR and ASDR with a value of 7.79 (95% UI 6.10 to 9.66) and 5.94 (95% UI 4.43 to 7.78), respectively (Fig. 2C, D). In this timeframe, ASPR, ASIR, and ASDR decreased in all SDI strata (Table 2, Fig. 2C, D).
The geographical variation in ASPRs of ALD among different countries/ territories in 2021 is illustrated in Figure 3B and Supplementary Table 3. In short, the ASPR of ALD was highest in the Republic of Moldova with an ASPR of 182.41 (95% UI 145.28 to 220.48), followed by Ukraine at 146.50 (95% UI 118.14 to 178.47), Mongolia at 145.63 (95% UI 115.28 to 174.84), and Turkmenistan at 130.18 (95% UI 100.91 to 157.40). 49 countries/ territories exhibited an uptrend, with the highest ascending trends observed in Kazakhstan (APC 1.74%; 95% CI 1.50 to 1.98%), Armenia (APC 1.60%; 95% CI 1.42 to 1.77%), Turkmenistan (APC 1.35%; 95% CI 1.29 to 1.41%), and Ukraine (APC 1.21%; 95% CI 0.90 to 1.53%) (Fig. 3C, Supplementary Table 3).
Alcohol-attributable primary liver cancer
In 2021, the highest burden of alcohol-attributable primary liver cancer in terms of ASRs was observed in Australasia, with an ASPR, ASIR, and ASDR of 3.77 (95% UI 3.03 to 4.61), 2.32 (95% UI 1.87 to 2.86), and 1.92 (95% UI 1.53 to 2.37), respectively (Table 3). From 2000 to 2021, Australasia (APC 3.52%; 95% CI 3.24 to 3.80%), Southern Latin America (APC 3.46%; 95% CI 3.32 to 3.60%), and High-income North America (APC 2.72%; 95% CI 2.58 to 2.86%) experienced the most notable changes in ASPR (Table 3). ASIR increased in two-thirds of regions, with the highest upward progression observed in Southern Latin America (APC 3.26%; 95% CI 3.03 to 3.50%), Australasia (APC 2.79%; 95% CI 2.54 to 3.04%), and High-income North America (APC 2.46%; 95% CI 2.32 to 2.60%). Similarly, ASDR exhibited the most pronounced increases in Southern Latin America (APC 3.09%; 95% CI 2.74 to 3.45%), Australasia (APC 2.47%; 95% CI 1.79 to 3.15%), and High-income North America (APC 2.30%; 95% CI 1.87 to 2.73%) (Table 3).
In terms of SDI, ASPR of alcohol-attributable primary liver cancer increased in high (APC 1.10%; 95% CI 1.05 to 1.16%), middle (APC 0.96%; 95% CI 0.89 to 1.04%), and low-middle SDI countries (APC 0.93%; 95% CI 0.89 to 0.97%) (Table 3, Fig. 2E). From the designated time frame, ASIR increased in low-middle (APC 0.90%; 95% CI 0.85 to 0.94%), middle (APC 0.61%; 95% CI 0.53 to 0.69%), and high SDI strata (APC 0.56%; 95% CI 0.51 to 0.62%) (Table 3). Similarly, ASDR increased in low-middle (APC 0.89%; 95% CI 0.70 to 1.09%), middle (APC 0.35%; 95% CI 0.18 to 0.52%), and high SDI countries (APC 0.27%; 95% CI 0.06 to 0.48%) (Table 3, Fig. 2F).
Classified by country, the ASPR of alcohol-attributable primary liver cancer was highest in Mongolia with an ASPR of 17.07 (95% UI 11.56 to 25.43), followed by Republic of Korea at 6.12 (95% UI 4.02 to 9.14), Gambia at 6.07 (95% UI 3.38 to 10.00), and Austria at 5.12 (95% UI 4.23 to 6.06) (Supplementary Fig. 2). From 2000 to 2021, Poland (APC 7.11%; 95% CI 6.33 to 7.89%), United Kingdom (APC 4.91%; 95% CI 4.66 to 5.16%), Sweden (APC 4.87%; 95% CI 4.49 to 5.25%), and Guatemala (APC 4.09%; 95% CI 3.70 to 4.48%) exhibited the highest rising trends. 111 countries/territories showed increasing trends of ASPR for liver cancer from alcohol (Supplementary Table 4).
DISCUSSION
Trends in alcohol use and its related health consequences have been evolving over the last few years, likely promoted by sociodemographic changes, cultural aspects, and the COVID-19 pandemic, among other factors [16,23]. In this study, we analyzed the trends in the global burden of some of the most frequent and striking consequences in health from alcohol misuse, AUD, ALD, and alcohol-attributable primary liver cancer, using the GBD 2021 [1]. In 2021, there were 158,470, 354,250, and 92,230 deaths from AUD, ALD, and alcohol-attributable primary liver cancer, respectively. From 2000 to 2021, around one-fourth of countries and territories exhibited an uptrend in the prevalence rate of ALD. The study also revealed a noteworthy rise in ALD and alcohol-attributable primary liver cancer burden both from the past two decades and during the COVID-19 pandemic. During the COVID-19 pandemic, females exhibited a higher increase in prevalence, incidence, and mortality from ALD compared to males, in contrast to prior to the pandemic.
Our findings are in line with trends observed from the GBD 2019 study [21,24], which highlighted the rising prevalence rates of ALD and alcohol-attributable primary liver cancer even while the prevalence rate of AUD declined. Our findings suggest that factors beyond alcohol consumption contribute to the rising prevalence of ALD and primary liver cancer [25,26]. Improved screening and diagnostic techniques allow for earlier and more accurate detection, while changes in disease registry systems may enhance the ability to capture current epidemiological trends, potentially leading to higher reported prevalence rates [27,28]. Furthermore, while overall AUD prevalence may be declining, higher-risk drinking behaviors, such as binge-drinking, among specific populations could be on the rise [29,30]. Even though the global burden of AUD declined, it is still markedly high, with over 111 million people living with AUD in 2021. The global decline masked an important regional variation in which Australasia, Oceania, and Western Sub-Saharan Africa exhibited an uptrend from age-adjusted incidence rates of AUD. Mortality from AUD decreased or remained stable in nearly all regions except increased in High-income North America. Of note, although AUD was more frequent in countries with high SDI, countries with lower SDI exhibited higher ASDRs from ALD, which could be explained by poorer healthcare access and availability of treatments and technologies, among other social and cultural variables [31,32]. ALD and AUD co-exist, with ALD being one of the most common alcohol-associated organ damage hence, policies to decrease alcohol use together with prevention and early detection of AUD are crucial for effectively reducing alcohol-related harm and ALD [14,33-35].
Our study found that during the COVID-19 pandemic, the change in incidence and mortality from AUD, ALD, and liver cancer from alcohol exhibited a lower increase compared to pre-pandemic trends, even though several studies reported an increasing rate of ALD and alcohol consumption at the greater extent during COVID-19 pandemic [36,37]. This observation may be explained by changes in access to alcohol, which was subjected to multiple factors, including the restriction of alcohol sales [38,39]. For example, in South Africa, alcohol was restricted in some regions during the COVID-19 pandemic.38 However, data from a cross-sectional study including over 3,000 individuals indicated that around a fifth of alcohol drinkers increased or started alcohol consumption during the pandemic [38]. A lag time between increased alcohol consumption and liver injury from alcohol, along with other factors, might be expected. Other relevant factors, such as the interaction between alcohol use and metabolic dysfunction (e.g., obesity, type 2 diabetes mellitus, arterial, and dyslipidemia), including MetALD, could also contribute to this rising trend of chronic liver disease and HCC [40-42]. Interestingly, our study found that from 2019 to 2021, females experienced a greater increase in ALD prevalence compared to males. This trend may be attributed to the rise in alcohol consumption among females during the COVID-19 pandemic [43]. In addition, self-underreporting of alcohol consumption is a well-recognized bias that impedes accurate tracking of epidemiological trends in AUD. This may partly explain the observed decline in AUD in our findings, especially during the pandemic, when limited healthcare access, heightened stigma in remote surveys, and disruptions in data collection likely played a role [44]. Moreover, whether AUD declines in female populations in areas where alcohol use among females is due to stigma remains an unproven hypothesis. Long-term data is needed to quantify the global effect of the COVID-19 pandemic on the alcohol-related disease burden, particularly liver disease, which accounts for nearly 90 percent of alcohol-related harm.
We acknowledge several limitations, which are common challenges encountered in GBD studies and relate to the availability and quality of primary data, mainly influenced by the efficacy of vital registration systems in each country [1,22]. Furthermore, the estimation methodology used by the GBD often leads to an underestimation of mortality, particularly in low-income countries, attributed to the absence of high-quality data and underreported risk factors attributable to the stigma around alcohol and its related health consequences. Additionally, GBD estimated AUD using ICD-10 codes rather than the Diagnostic and Statistical Manual of Mental Disorders, 5th edition. This can lead to an underestimation of the true burden of AUD, ALD, and alcohol-attributable liver cancer in these regions [1,45]. The report on alcohol use also tends to be underestimated [46]. Also, we performed our analysis based on geographical and SDI strata, which comprise many factors of social determinants of health; however, it is not fully comprehensive. In addition, the GBD analysis framework is currently limited to attributing a single cause to a specific outcome, preventing the inclusion of co-variation with other relevant risk factors. Thus, future modeling studies should be conducted, incorporating other comorbidities and determinants of health, such as race, ethnicity, age, socio-economic status, cultural factors, and other relevant risk factors for liver disease, such as viral hepatitis and metabolic dysfunction [41,47-50].
In conclusion, our study reported a high burden of AUD, ALD, and liver cancer attributable to alcohol, including an increased prevalence rate of liver cancer from alcohol from 2000 to 2021. Prevalence, incidence, and mortality of ALD increased from 2019 to 2021, with a steeper trend in females compared to males. Given that 49 countries exhibited an uptrend in ALD prevalence rates and 111 countries were found to have an uptrend in liver cancer prevalence rates from alcohol consumption between 2000 and 2021, it is essential to implement comprehensive strategies globally. These strategies should focus on reducing alcohol intake, preventing AUD, and effectively treating its health consequences, including ALD and HCC, in all countries and territories worldwide.
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