Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors

Abstract

Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5 litres in 2005 to 6.4 litres in 2016 and is projected to increase further to 7.6 litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.

Fig. 1. Estimated age-standardized death rates (ASDRs) for alcohol-associated cirrhosis per 100,000 population in 2019, by country/territory.

Data for the age-standardized death rate in 2019 were estimated by the Global Burden of Disease study 2019 for each country/territory. These data were obtained from the GBD Results Tool, which is maintained by the Institute for Health Metrics and Evaluation. Where data for certain countries or regions were unavailable, the Global Burden of Disease Study 2019 results depended on modelling and past trends, potentially resulting in discrepancies in the accuracy of the data.

Fig. 2. Estimated age-standardized death rates (ASDRs) for alcohol-associated liver cancer per 100,000 population in 2019, by country/territory.

Data for the age-standardized death rate in 2019 were estimated by the Global Burden of Disease Study 2019 for each country/territory. These data were obtained from the GBD Results Tool maintained by the Institute for Health Metrics Evaluation. Where data for certain countries or regions were unavailable, the Global Burden of Disease Study 2019 results depended on modelling, potentially resulting in discrepancies in the accuracy of the data. These ASDRs may be an underestimate owing to underreporting, especially in countries/regions with a lack of access to the diagnostic services required for the diagnosis of liver cancer.

Fig. 3. Pathogenesis of alcohol-associated cirrhosis and alcohol-associated hepatocellular carcinoma.

Alcohol is metabolized to acetaldehyde by alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1) within hepatocytes, resulting in the formation of reactive oxygen species (ROS), which activates hepatic stellate cells and leads to fibrosis in conjunction with acetate. Acetaldehyde triggers inflammation, forms DNA adducts and results in DNA hypomethylation, which leads to hepatocarcinogenesis. Formation of ROS also leads to the formation of DNA adducts via lipid peroxidation and subsequent carcinogenesis. Alcohol induces microbial dysbiosis and alters gut permeability, enabling translocation of lipopolysaccharide (LPS) and gut bacteria to the liver. This translocation results in the activation of Kupffer cells and production of pro-inflammatory cytokines and chemokines, which promotes fibrosis and activation of the oncogenic interleukin-6 (IL-6)–signal transducer and activator of transcription 3 (STAT) and tumour necrosis factor (TNF)–nuclear factor-κB (NF-κB) pathways.

Fig. 4. Risk factors for alcohol-associated cirrhosis and alcohol-associated hepatocellular carcinoma (HCC).

Older age, degree and pattern of alcohol consumption, diabetes, obesity, gut microbial dysbiosis, genetic susceptibility and smoking are risk factors for the development of alcohol-associated cirrhosis and alcohol-associated HCC.