Epidemiological Realities of Alcoholic Liver Disease: Global Burden, Research Trends, and Therapeutic Promise

Abstract

Globally, alcohol consumption contributes to more than 3 million deaths each year. While much of its ramifications is preventable, a coherent public health discourse on how to limit alcohol-related harm has been overdue. By synthesizing information from national and global databases, we show in this analysis that alcohol consumption level and alcohol-attributable burden of diseases, particularly alcoholic liver disease (ALD), are intimately linked to national income distribution, cultural norms, religion, sex, age, and health status. Prevalence and burden of ALD are positively associated with economic standing in most countries, which necessitate active governmental control via cost-effective policies, such as the best buys proposed by the World Health Organization. To date, a number of critical questions remain unanswered over the molecular mechanisms underlying ALD pathophysiology; the insights gained thereof should provide new opportunities for the advancement of novel diagnostic and management strategies. In comparison with other prevailing liver diseases (e.g., viral hepatitis and nonalcoholic fatty liver disease), governmental support to ALD investigation has been sluggish in most Western countries and China, resulting in a dearth of breakthroughs on both the basic and clinical research fronts in the past decades. Emerging foci of clinical trials for ALD therapy include empirical use of probiotics, antioxidants, growth factors, monoclonal antibodies against key inflammatory mediators, and technology-enhanced behavioral interventions. In this article, we seek to provide a comprehensive analysis on the progress and challenges in tackling ALD as a global health problem, with particular emphasis on global disease burden, socioeconomic influences, research trends, government roles, and future therapies.

Figure 1

Global status of alcohol consumption and prevalence of alcohol-attributable disorders and liver complications. (A) Global status of alcohol per capita (APC; 15+) consumption (in liters of pure alcohol; 2016) (data source: World Health Organization13). (B) Global prevalence of alcohol use disorders (AUDs) (%) in 2016 (data source: World Health Organization13). (C, D) Global estimates on disability-adjusted life years (DALYs) by cirrhosis and liver cancer due to alcohol use in 2016 (per 1,000 persons) (data source: World Health Organization14).

Figure 2

Correlation analysis on national income distribution, alcohol consumption, and alcoholic liver cirrhosis. (A) Correlation analysis on gross national income (GNI) per capita (Atlas method, current US$) and male/female alcohol-attributable fractions of liver cirrhosis (AAF%) in 2016. (B) Correlation analysis on GNI per capita and AUD prevalence (%) in 2016. (C) Correlation analysis on global status of APC (15+) consumption and male/female liver cirrhosis AAFs or AUD prevalence in 2016 (data source: World Bank national accounts data, OECD national accounts data, and World Health Organization13).

Figure 3

Conceptual framework on government policies on the control of alcohol abuse and alcohol-related public health problems. To effectively reduce alcohol use across the life span of individuals, proper governmental control policies, such as increasing alcohol price/tax, regulating the physical availability of alcohol, and restricting alcohol marketing, are recommended by the World Health Organization. Those “best buy” interventions can decrease disease and social burdens (e.g., traffic accidents, criminal justice, and health care) caused by alcohol consumption.

Figure 4

Mechanisms involved in the pathophysiology of alcoholic liver disease (ALD). In the human body, ethanol is metabolized by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), generating toxic aldehyde and reactive oxygen species (ROS) to elicit local oxidative stress and inflammation. Hepatic lipid metabolism is disrupted by alcohol consumption to induce steatosis, causing alcoholic fatty liver and alcoholic steatohepatitis (ASH). Excessive alcohol also provokes gut microbiota dysbiosis to produce toxins such as lipopolysaccharides (LPS) and other pathogen-associated molecular patterns. Those stimuli will activate hepatic stellate cells (HSCs), leading to extracellular matrix production, and subsequent liver fibrosis, cirrhosis, and even hepatocellular carcinoma. CYP2E1, cytochrome P450 2E1; DAMPs, damage-associated molecular patterns; NLRs, nucleotide-binding oligomerization domain (NOD)-like receptors; TLRs, toll-like receptors.

Figure 5

Algorithm for diagnosis and therapeutic decision of patients with ALD. Heavy drinks are under clinical diagnosis for AUD, ALD, or ASH. Noninvasive elastography or liver biopsy is needed in some cases to make precise diagnosis and therapeutic decision.

Figure 6

Comparison on national grant support for basic research in the fields of hepatology and ALD in major Western countries and China (1986–2019). Changes in number of funded projects and total funding amounts of all liver-related projects and corresponding percentage of ALD projects in those projects from the US [National Institutes of Health (NIH)], China [National Natural Science Foundation of China (NSFC)], Japan [Grants-in-Aid for Scientific Research (KAKENHI)], Australia [National Health and Medical Research Council (NHMRC)], Germany [German Research Foundation (DFG)], the UK [Research Councils UK (RCUK)], France [French National Research Agency (ANR)], and Spain [El Instituto de Salud Carlos III (ISCIII)]. Information on funded projects was manually collected and selected by searching project titles with the keywords “liver,” “hepatic,” “hepatitis,” “hepatoma,” “cirrhosis,” “hepatocyte,” “Kupffer,” and “Wilson” in the NSFC information system (https://isisn.nsfc.gov.cn/egrantweb/), NIH Project Reporter system (https://projectreporter.nih.gov/reporter.cfm/), KAKENHI database (https://kaken.nii.ac.jp/), NHMRC Research Funding Statistics and Database (https://www.nhmrc.gov.au/funding/data-research/research-funding-statistics-and-data), German Project Information System (https://gepris.dfg.de/gepris/OCTOPUS?language=en), RCUK Gateway to Research System (https://gtr.ukri.org/), ANR Funded Projects and Impact Database (https://anr.fr/en/funded-projects-and-impact/funded-projects/), and ISCIII Fondo de Investigación en Salud (https://portalfis.isciii.es/es/Paginas/inicio.aspx) in March, 2020. The Spanish keywords used were “hígado,” “hepático,” “hepática,” “hepatitis,” “hepatocito,” “hepatoma,” “cirrosis,” “Kupffer,” and “Wilson.”

Figure 7

Profiles of publications of liver-related articles in the Web of Science Core Collection and in top journals of multidiscipline, medicine, and gastroenterology from 1986 to 2019. (A) Statistics for published hepatology articles and (B) author address percentage during 1986–2019. Data were collected by searching Web of Science Core Collection with the keyword “liver” during 1986–2019 at https://apps.webofknowledge.com/. (C, D) Statistics and author address percentage of all liver-related articles and ALD-related articles in top journals of medicine (New England Journal of Medicine, Lancet, Journal of the American Medical Association, British Medical Journal), multidiscipline (Nature and Science), cell biology (Cell), and gastroenterology (Gastroenterology, Gut, Hepatology, Journal of Hepatology, and American Journal of Gastroenterology) during 2000–2019. Data were collected by searching for the following items on Web of Science Core Collection (http://apps.webofknowledge.com/): “Year Published = 2000–2019” AND “Publication Name = New England Journal of Medicine” (or other 11 top journal names) in April 2020. We only counted research articles and invited reviews from those journals. All searched hits were manually selected by Dr. Jia Xiao and Dr. Fei Wang to ensure compliance with topic suitability and other vetting criteria.