Alcohol dependency (AD) is a complex addictive disorder, affecting millions of individuals around the world each year. AD is considered a worldwide public health problem with a direct causal relationship between alcohol consumption and more than 60 different types of disease and injury. Regarding this, the ICD-10 (International Classification of Disease 10th Revision) has reported eight causes of death related to alcohol consumption (Table 1). Most of these causes are related to the amount and time of exposure to alcoholic beverages. According to the World Health Organization, the average alcohol consumption per capita in adults is 5.1 liters per year, though mean consumption varies worldwide. While in some countries, like Saudi Arabia, alcohol consumption (liters per capita per year) is 0.0, in other countries such as Luxembourg the consumption reaches 17.54 [1].

The impact and consequences of AD and alcohol abuse have elevated economical costs, as well as negative health and social implications. The most direct health influence of ethanol consumption is reflected in a systemic level; thereby moderate ethanol consumption has been related to a reduced cardiovascular disease, favorable lipid profile and less thrombogenic platelet function [2]. On the other hand, elevated amounts of alcohol intake lead to hepatic damage.

Although the mechanisms by which ethanol causes liver damage have been well described, some facts remain to be elucidated. The risk, severity and prognosis of ethanol-mediated liver diseases generally depend on the amount, frequency, and duration of alcohol consumption, as well as the continued presence of liver inflammation, diet, nutritional status and genetic make-up of the host. In this matter, alcoholic steatosis (AS) is the initial pathology found in early stages of the natural history of alcoholic liver disease (ALD). AS is characterized by the accumulation of lipids in the liver. Steatosis caused by alcohol is clinically considered as benign since it is reversible if the stimulus is removed. The progression to alcoholic steatohepatitis (ASH) represents the key step in the development of ALD. Only a small portion of heavy drinkers develop a severe form of the disease, suggesting the involvement of other factors modifying ALD onset and presentation [3].

Alcohol is identified as a harmful agent to the liver, and hepatic stellate cells (HSC) are activated in response to this injury. Activated HSC are recognized as fibrogenic cells and lead to deposition of collagen (particularly collagen type I). HSC are also regulated in a paracrine manner by acetaldehyde and reactive oxygen species (ROS), produced by the metabolism of ethanol in surrounding hepatocytes. Activated Kupffer cells secrete pro-inflammatory cytokines, linking apoptosis in the liver to inflammation [4].

“Programmed cell death”, also called apoptosis, plays an important role in the pathogenesis of chronic liver disease. Whenever there is an acute presentation of the disease, it is possible to observe massive hepatocyte apoptosis. This phenomenon induces progressive fibrosis, which is the hallmark of chronic liver damage and, therefore could result in liver failure, cirrhosis, and hepatocellular carcinoma.

To objectively assess damage degree in the hepatic parenchyma, completion of a histological study is required. In steatohepatitis, findings in the lamellae include hepatocyte steatosis, ballooning, apoptosis, and lobular inflammatory infiltrate [4]. When ALD is established, an accumulation of reducing equivalents in the cytosol and the rates of fatty acids biosynthesis and subsequent esterification into triglycerols are markedly increased [5].

The World Health Organization reports about two billion alcohol consummers worldwide and 76.3 million people with diagnosable alcohol use disorders [1]. Globally, alcohol causes 3.2% deaths for all causes (1.8 million deaths annually) and accounts for 4.0% of disease burden [2].

Excessive ethanol consumption is an important preventable cause of morbidity. The association between ethanol intake and alcoholic liver disease has been well documented, though liver cirrhosis develops only in a small proportion of heavy drinkers. Twenty percent of alcoholics and heavy drinkers develop fatty liver and only 10 to 15 percent of these will develop cirrhosis. The point prevalence of cirrhosis is 1% in people who drink 30 to 60 g of alcohol a day, and up to 5.7% in those consuming 120 g daily. In this matter, mortality studies have demonstrated that heavy drinkers and alcoholics die from cirrhosis at a much higher rate than the general population [6].

A clear aggregated environmental risk factor for the development of cirrhosis attributable to alcohol consumption is infection with hepatitis C virus (HCV). The risk of cirrhosis in humans infected with HCV increases proportionally with consumption of more than 30 g of alcohol per day; as mentioned above, the highest risk is associated with consumption of more than 120 g per day. Other factors, such as sex, genetic characteristics, and environmental influences (including chronic viral infection), play a role in the genesis of ALD [7].

In addition, alcoholism is a multifactorial brain disorder, according to the DSMIV (Diagnostic and Statistical Manual of Mental Disorders Fourth Revision), therefore the approach should be addressed on neurobiological and genetic strategies for the prevention, diagnosis, and treatment of alcoholism. The identified factors that contribute to the development of alcoholism are included in a social environment (i.e., parents, family, friends, peers, community, society). Possible social co-determinants such as poverty, social inequality, and easy availability of alcoholic beverages might establish alcoholism development.

Several studies indicate that AD has a genetic component. The heritability of alcohol dependence is rather high, ranging between 50% and 60%, though it has been shown to be a complex polygenic disorder. There have been associated specific genes and polymorphisms that affect the risk of alcohol use disorders. These genes involve expression of enzymes responsible for alcohol metabolism, such as alcohol dehydrogenase and aldehyde dehydrogenase; those associated with disinhibition, and those that confer a low sensitivity to alcohol [8].

Genes have been proposed to be involved in a predisposition to ALD development and alcohol use disorders. Combined genetic information about these two entities might enhance alcohol related diseases.

Mechanisms implicated in alcohol-induced liver damage involve many biochemical reactions with different simultaneous pathways interacting with each other. These mechanisms involve enzymes, ROS, endotoxins, cytokines, immune system cells, and genetic predisposition to develop alcoholic liver disease [17,18]. Alcohol is metabolized by oxdative reactions to acetaldehyde and then converted to acetate through alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH). ADH is quantitatively the most important enzyme capable of catalysing the conversion of ethanol to acetaldehyde.

It has been proposed that ethanol metabolism causes proteasome inhibition [19] and that the initial molecular changes of ethanol injury are the reduction of both phosphorylation and activity of AMP-dependent protein kinase (AMPK). This contributes to the development of fatty liver by allowing increased activity of acetyl-CoA carboxylase [20,21]. Although alcoholic fatty liver resolves with alcohol abstinence, steatosis predisposes to the development of hepatic fibrosis and cirrhosis in people with continued pathological drinking patterns (Figure 1) [6].

Wu et al. mention that several mechanisms contribute to alcohol-induced liver injury, and that ethanol-induced oxidative stress is likely to arise from several sources, including CYP2E1, mitochondria, and activated Kupffer cells [17,22]. A central pathway appears to be the induction of cytochrome P450 2E1. It metabolizes and activates many toxicological substrates, including ethanol, to more reactive and toxic products [23]. This mechanism plays a role in creating a harmful condition known as oxidative stress, defined as the result of an imbalance between pro-oxidant and antioxidant systems [20]. This enhances the formation of free radicals which act in the lipidic wall membrane ongoing lipid peroxidation.

ROS are intermediates in cell signaling pathways that alter gene expression and lead to cell proliferation, migration, and apoptosis; thus contribute to the development of chronic ethanol-induced liver injury [23]. When alcohol is consumed, CYP2E1 generates acetaldehyde as well as ROS in the cytosol of the cell, leading to an increase in oxidative stress with a probable mitochondrial origin. ROS are toxic to cells because they can react with most cellular macromolecules by inactivating enzymes or denaturing proteins, which causes DNA damage [6].

When alcohol is metabolized to acetaldehyde, the oxidized form NAD converts to the reduced form NADH. This reaction generates an excess of reduced equivalents which stimulates lipid biosynthesis [24]. Alcohol exposure increases nitrosative stress with elevated levels of ethanol-inducible CYP2E1, nitric oxide synthase, nitrite and mitochondrial hydrogen peroxide. Ethanol can also induce and/or activate inducible nitric oxid synthase (iNOS), which plays a key role in worsening alcohol-mediated hepatotoxicity. Moreover, the overexpression of CYP2E1 aggravates hepatic injury. Besides, expression of cytokeratins 8 and 18 can be considered as biomakers for ALD progression [25].

Alcohol intake also increases gut permeability, allowing bacterial endotoxins to enter the bloodstream and liver, where it can activate certain immune cells. Lipopolysaccharide (LPS) is an important activator of Kupffer cells requiring three cell proteins to complete the process: CD14, TLR4, and MD2. Activated Kupffer cells are responsible for an increased expression of TNFα and multiple inflammatory cytokines [26]. TNF-α is a mediator, not only in the early stages of fatty liver disease but also in the transition to more advanced stages of liver damage [27]. This activation is one of the earliest liver responses to injury. TNF-α is considered one of the most important cytokines involved in the pathogenesis of alcoholic liver bruise. Evidence indicates that disruption of the TNF-αR1 gene or treatment with a TNF-α neutralizing antibody, reduces alcoholic liver injury in mice.

Alcohol-induced liver damage also depends on the host immune system susceptibility. Several studies have suggested that immune response plays a role in alcoholic liver disease. Pritchard et al. suggested the hypothesis that activation of the complement is required for the development of ethanol-induced fatty liver. They found that C3 contributed to accumulation of triglyceride in the liver, while C5 was involved in inflammation and injury to hepatocytes [28]. Another study demonstrated that NK cells may also directly ameliorate hepatic fibrosis, first by releasing antifibrotic cytokines (interferon [IFN]α and IFNγ), and second by killing activated stellate cells. Ethanol impairs the ability of NK cells to kill activated HSC. As a result, it could remove this break in the development of fibrosis (Figure 2) [29].

Moreover, there are some underlying conditions in which ethanol can cause damage in a broader manner. Thereby, ethanol and chronic HCV infection synergistically accelerate liver injury. The process by which this occurs remains unclear, but it is believed that chronic liver inflammation is the keyhole to this pathogenesis. In these cases, there is a relationship between increased alcohol intake and decreased response to interferon (IFN) therapy for HCV [7].

Chronic consumption of alcohol elevates iron levels in the body, not only when consuming iron-rich beverages like wine, but also stimulating exogenous iron absorption from food.

In general, cells have protective mechanisms to attenuate harm caused by ROS and the oxidative process. These mechanisms include enzymes like SOD (Superoxide Dismutase), catalase, glutathione peroxidase (which removes H₂O₂), glutathione transferase, ferritine (removes metals like iron that promotes oxidative stress), and low molecular weight antioxidants such as vitamin E, vitamin C, vitamin A, uric acid, and bulirubin. However, the production of oxidative species and reduced equivalents is more elevated than defense mechanisms, due to the fact that alcohol inhibits antioxidants [30].

High amount of chronic consumption pattern of ethanol increases the risk to develop other health problems. This pattern has a wide variety of adverse effects. It has been already described that ALD involves significant crosstalk among intracellular signaling events in the liver. Overall, inflammatory and innate immune responses in Kupffer cells are activated by elevated gut-derived plasma endotoxin levels [6]. It increases ROS which induces damage and metabolites production, such as acetaldehyde or lipid peroxidation products, that contribute to activation of HSC (the key cell type involved in liver fibrosis) [21]. Complications start when these events diminish the functional hepatocytes. Considering all patients with ALD as a single group, the average 1- and 5-year survival rates are approximately 80 and 50%, respectively [28]. Liver cirrhosis is the most severe form of ALD. Scar tissue replaces normal hepatocytes, disrupting blood flow. When the liver becomes fibrotic and cirrhotic, the number of functional hepatocytes decreases, and the liver loses its capacity to remove toxic substances from the blood [32]. Patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality greater than 60%. The prognosis of individual patients with ALD depends on the degree of pathological injury, the patient's nutritional status, the presence of complications of advanced disease, other comorbid conditions, such as HCV infection, and the patient’s inability to eliminate destructive drinking patterns. Alcoholic cirrhosis also appears to be an independent risk factor for hepatocellular carcinoma [34]. One month mortality in patients with spontaneous hepatic encephalopathy is approximately 50% and 75% in those with hepatorenal syndrome; the median survival of patients with hepatorenal syndrome is less than two weeks. Comparing alcoholic cirrhosis to other etiologies, it is known that alcohol in Japanese society accounts for 13.6 percent of all cases of cirrhosis [11] while Hepatitis B virus (HBV) and HCV infection account for 13.9% and 60.9% of cases respectively. Other causes were primary biliary cirrhosis with 2.4% and autoimmune hepatitis with 1.9% [37].

Alcoholic hepatitis is perhaps the most overwhelming manifestation of alcoholic liver disease. Up to 40% of patients with severe alcoholic hepatitis die within the first 6 months after the onset of the clinical syndrome. It is well known that more severe forms of alcoholic hepatitis are associated with higher mortality rates [38]. Among alcoholic hepatitis signs jaundice and fever may resolve in alcoholic hepatitis within several weeks after discontinuation of alcohol intake, but ascites and hepatic encephalopathy might persist for months to years. Mortality rate in alcoholic hepatitis is about 50% in severe cases. If the heavy drinking pattern continues, 40 percent will develop cirrhosis. When clinical symptoms of encephalopathy appear, ammonia levels in the brain may increase more than twenty fold, this happens in patients with advanced stages of encephalopathy, resulting from chronic liver failure. Ammonia remains the key gut-derived neurotoxin implicated in the pathogenesis of hepatic encephalopathy [39].

There is a wide range of therapeutic options for treating ALD and alcohol use disorders. The aim of all therapeutic strategies for ALD is to improve liver function. In alcoholic patients the goal attempts to reduce ethanol intake significantly, looking forward abstinence, thus avoiding further hepatic damage.

Ethanol consumption is widely accepted worldwide and it is sometimes traduced into substance abuse. It causes global public health problems, covering social aspects as well as psychological, economical and family ones, among others.

When alcohol consumption affects an individual’s health, molecular mechanisms inducing liver damage begin to occur. These processes have been described broadly and therapies developed for these diseases are focused on avoiding alcohol abuse and improvement of liver function, once a diagnosis of ALD has been made.

Nevertheless, there are genetic factors that could predispose to the development of alcoholism or ALD. The identification of certain polymorphisms associated to these entities has been possible. Currently, there is a lengthy list of treatment strategies. Both conditions have multifactorial origin, so each factor involved is a target for the development of new therapies. New drug research is needed since currently available treatments are not as effective as expected, for after a year of alcohol consumption cessation, pathological drinking patterns tend to reappear.