Alcohol and toxicity
Authors: Ivan Rusyn, Ramon Bataller
Journal: Journal of Hepatology (2013)

Reply to: "The autophagic response to alcohol toxicity: The missing layer"Journal of HepatologyVol. 59Issue 2PreviewWe appreciate the interest of Eid et al. [1] in the Hepatology Snapshot on "Alcohol and toxicity" [2]. The authors posit that autophagy, a physiological mechanism that is ubiquitous and critical for maintaining balance in synthesis, degradation, and recycling of proteins, lipids and other macromolecules, represents the central mechanism that connects key toxicity mediators and molecular mechanisms with alcohol-induced disturbances in target tissues. Full-Text PDF Open AccessThe autophagic response to alcohol toxicity: The missing layerJournal of HepatologyVol. 59Issue 2PreviewWe read with interest the manuscript by Rusyn and Bataller [1]. The authors summarized the various mechanisms of alcohol-induced toxicity and organ damage in a seven-layered diagram. In this diagram, the authors demonstrated that alcohol toxic mediators, as acetaldehyde and ROS, activate several cellular molecular mechanisms such as hypoxia, ER stress, and DNA damage (layer 4), resulting in pathological changes in most body organs (layer 5). These changes include steatosis, apoptosis/necrosis, fibrosis, and cancer. Full-Text PDF Open Access Excessive alcohol intake is a major public health challenge worldwide and has been identified as one of the main determinants of a variety of non-communicable diseases [[1]Parry C.D. Patra J. Rehm J. Alcohol consumption and non-communicable diseases: epidemiology and policy implications.Addiction. 2011; 106: 1718-1724Crossref PubMed Scopus (204) Google Scholar]. The World Health Organization (WHO) estimates that 4.5% of the global burden of disease and injury, and 4% of all deaths worldwide are attributable to alcohol [[2]World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar]. Alcohol is the leading risk factor for death among males aged 15–59 years, particularly in Eastern Europe [2World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar, 3Zaridze D. Brennan P. Boreham J. Boroda A. Karpov R. Lazarev A. et al.Alcohol and cause-specific mortality in Russia: a retrospective case-control study of 48,557 adult deaths.Lancet. 2009; 373: 2201-2214Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar]. Toxic and other adverse effects of alcohol on organs and tissues in humans (see Figure) are largely a consequence of its metabolism to acetaldehyde, and associated formation of reactive oxygen and nitrogen species, depletion of co-factors (e.g., NAD+), and impairment in energy homeostasis [[4]Zakhari S. Overview: how is alcohol metabolized by the body?.Alcohol Res Health. 2006; 29: 245-254PubMed Google Scholar]. Because of the considerable redundancy in the oxidative enzymatic pathways (alcohol dehydrogenases, CYP2E1, and catalase) that can convert alcohol to acetaldehyde, most tissues are capable of alcohol metabolism, even though the liver is the primary site. Likewise, acetaldehyde dehydrogenases are ubiquitous in the mitochondria. A minor, non-oxidative, pathway of alcohol metabolism is to fatty acid ethyl ester (via fatty acid ethyl ester synthase) and phosphatidyl ethanol (via phospholipase D). Alcohol impacts the integrity of the gastrointestinal mucosal barrier. This results in the translocation, via the portal blood flow, of the gut bacteria-derived lipopolysaccharide (endotoxin) and other molecules to the liver, and activation of the innate immune response. The molecular and cellular sequelae of the toxic mediators of alcoholic injury take many forms. Acetaldehyde and oxidants are highly reactive molecules that can damage DNA, proteins, and lipids. Changes in hepatic respiration and lipid metabolism lead to tissue hypoxia and impairment in the mitochondrial function. Secondary effects include disruption of signaling pathways and ion channel function, unfolded-protein response, and oxidative stress, as well as activation of adaptive immune response largely triggered by acetaldehyde-protein adducts. Cell death triggers additional innate immune response, activation of fibrogenesis, and tissue repair. In addition to pro-inflammatory mediators, other signaling molecules, such as neurotransmitters, are affected by alcohol. Gross pathological changes associated with alcohol drinking include most or all, depending on the affected tissue, of the following: fat accumulation (steatosis), inflammation, necrosis, and fibrosis [[5]Gao B. Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585Abstract Full Text Full Text PDF PubMed Scopus (1368) Google Scholar]. Impairment of organ function and carcinogenesis are most advanced pathological effects and are associated with organ dysfunction and increased mortality. As a consequence, alcoholic beverages and ethanol in alcoholic beverages are classified by the WHO International Agency for Research on Cancer as "carcinogenic to humans" (Group 1) [[6]Baan R. Straif K. Grosse Y. Secretan B. El Ghissassi F. Bouvard V. et al.Carcinogenicity of alcoholic beverages.Lancet Oncol. 2007; 8: 292-293Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar]. Alcohol is highly diffusible through cell membranes and is metabolized by most tissues. Thus, its toxicity affects most organs. Because the liver is the major site of alcohol metabolism, it is one of the major targets for alcohol-induced organ damage. Alcoholic liver diseases include steatosis, different subtypes of steatohepatitis, cirrhosis, and hepatocellular carcinoma [[5]Gao B. Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585Abstract Full Text Full Text PDF PubMed Scopus (1368) Google Scholar]. Of these, cirrhosis of the liver is the third leading (at 16.6%) cause of alcohol-attributable deaths worldwide [[2]World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar]. In addition, other anatomical sites in the aero-digestive tract are adversely affected by alcohol, with most important morbidity and mortality due to malignant tumors, all causally related to alcohol consumption, of the oral cavity, pharynx, larynx, esophagus, and colorectum [[6]Baan R. Straif K. Grosse Y. Secretan B. El Ghissassi F. Bouvard V. et al.Carcinogenicity of alcoholic beverages.Lancet Oncol. 2007; 8: 292-293Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar]. In the pancreas, toxic metabolites of alcohol cause acinar cell injury leading to pancreatitis and subsequent fibrosis [[7]Apte M.V. Pirola R.C. Wilson J.S. Mechanisms of alcoholic pancreatitis.J Gastroenterol Hepatol. 2010; 25: 1816-1826Crossref PubMed Scopus (84) Google Scholar]. The cardiovascular system is second only to gastrointestinal organs in toxic effects of alcohol [1Parry C.D. Patra J. Rehm J. Alcohol consumption and non-communicable diseases: epidemiology and policy implications.Addiction. 2011; 106: 1718-1724Crossref PubMed Scopus (204) Google Scholar, 2World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar]. Hypertension, ischemic heart disease, stroke, cardiomyopathy, and myocarditis, as well as various arrhythmias, have been associated with alcohol abuse. The linkages between alcohol use and neuropsychiatric disorders have also been established as causal (e.g., for major depression) [[8]Boden J.M. Fergusson D.M. Alcohol and depression.Addiction. 2011; 106: 906-914Crossref PubMed Scopus (726) Google Scholar]. In addition, neurobehavioral impairment due to alcohol intoxication is a major contributor to deaths from violence, road traffic accidents, and injuries [[2]World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar]. In the kidney, excessive alcohol intake has been associated with IgA glomerulonephritis, acute nephropathy, and kidney graft failure [[9]Schaeffner E. Ritz E. Alcohol and kidney damage: a Janus-faced relationship.Kidney Int. 2012; 81: 816-818Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar]. Adverse effects of alcohol on human reproduction and development span the wide range of pathological conditions from impaired fertility to premature and low-weigh births, and fetal alcohol syndrome spectrum disorders [[2]World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar]. The addition of breast cancer to the list of cancers causally related to alcohol consumption suggested that the proportion of malignancies attributable to alcohol consumption is higher than previously estimated [[6]Baan R. Straif K. Grosse Y. Secretan B. El Ghissassi F. Bouvard V. et al.Carcinogenicity of alcoholic beverages.Lancet Oncol. 2007; 8: 292-293Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar]. Indeed, recent studies show that up to 5% of breast cancers are attributable to alcohol in northern Europe and North America for a total of approximately 50,000 alcohol-attributable cases of breast cancer worldwide [[10]Seitz H.K. Pelucchi C. Bagnardi V. La Vecchia C. Epidemiology and pathophysiology of alcohol and breast cancer: update 2012.Alcohol Alcohol. 2012; 47: 204-212Crossref PubMed Scopus (186) Google Scholar]. Factors affecting susceptibility to alcohol toxicity include genetics, gender, lifestyle/nutrition, exposure to environmental chemicals and drugs, and co-morbidities. Variations in genes encoding metabolic pathways for alcohol or triglycerides, as well as many other genes that may be involved in the pathogenesis or protection from alcohol-induced toxicity, modify the individual's response to alcohol abuse and disease outcomes [4Zakhari S. Overview: how is alcohol metabolized by the body?.Alcohol Res Health. 2006; 29: 245-254PubMed Google Scholar, 5Gao B. Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets.Gastroenterology. 2011; 141: 1572-1585Abstract Full Text Full Text PDF PubMed Scopus (1368) Google Scholar, 6Baan R. Straif K. Grosse Y. Secretan B. El Ghissassi F. Bouvard V. et al.Carcinogenicity of alcoholic beverages.Lancet Oncol. 2007; 8: 292-293Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar]. The effect of gender varies by disease outcome with females being more susceptible to alcoholic liver disease, but most alcohol-attributable deaths occur in males [1Parry C.D. Patra J. Rehm J. Alcohol consumption and non-communicable diseases: epidemiology and policy implications.Addiction. 2011; 106: 1718-1724Crossref PubMed Scopus (204) Google Scholar, 2World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar]. Dietary (e.g., high-fat consumption, patterns of alcohol intake), life style (e.g., cigarette smoking, drugs of abuse), and environmental (e.g., nitrosamines, metals, and chlorinated solvents) factors also affect both morbidity and mortality related to alcohol abuse. Obesity, viral infections, iron accumulation, and other pro-inflammatory conditions, as well as concomitant use of certain drugs (e.g., acetaminophen, isoniazid, and methotrexate), also compound morbidity and mortality due to alcohol abuse. Finally, while overwhelming evidence exists to conclude that consumption of alcoholic beverages is harmful to human health, many studies observed some beneficial effects of modest alcohol consumption (usually defined as 1–2 servings/day) [[1]Parry C.D. Patra J. Rehm J. Alcohol consumption and non-communicable diseases: epidemiology and policy implications.Addiction. 2011; 106: 1718-1724Crossref PubMed Scopus (204) Google Scholar]. Health conditions that have been associated with "beneficial effects" of alcohol on mortality include cardiovascular diseases (e.g., myocardial infarction) and chronic kidney disease [1Parry C.D. Patra J. Rehm J. Alcohol consumption and non-communicable diseases: epidemiology and policy implications.Addiction. 2011; 106: 1718-1724Crossref PubMed Scopus (204) Google Scholar, 9Schaeffner E. Ritz E. Alcohol and kidney damage: a Janus-faced relationship.Kidney Int. 2012; 81: 816-818Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar], yet such protection disappears with heavy drinking occasions [[2]World Health Organization Global status report on alcohol and health. WHO Press, Geneva, Switzerland2011Google Scholar]. No "safe" amount of alcohol consumption has been found for cancer; even consumption of two drinks per day causes a significant increase in risk [[6]Baan R. Straif K. Grosse Y. Secretan B. El Ghissassi F. Bouvard V. et al.Carcinogenicity of alcoholic beverages.Lancet Oncol. 2007; 8: 292-293Abstract Full Text Full Text PDF PubMed Scopus (677) Google Scholar]. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.