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Alcohol

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Introduction

Alcohol, most commonly referred to by the chemical name ethanol (C2H5-OH), is a psychoactive drug that is the active ingredient in drinks such as beer, wine, and distilled spirits (hard liquor). It is one of the oldest and most common recreational substances, causing the characteristic effects of alcohol intoxication ("drunkenness"). Among other effects, alcohol produces a mood lift and euphoria, decreased anxiety, increased sociability, sedation, impairment of cognitive, memory, motor, and sensory function, and generalized depression of central nervous system function. Ethanol is only one of several types of alcohol, but it is the only type of alcohol that is found in alcoholic beverages or commonly used for recreational purposes; other alcohols such as methanol and isopropyl alcohol are significantly more toxic.

The same dose of alcohol per unit of body weight can produce very different blood alcohol concentrations in different individuals because of the large variations in proportions of fat and water in their bodies, and the low lipid to water partition coefficient of ethanol.

The following section will be providing an overview of alcohol metabolism as well as its mode of action and its relationship with disease.

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Alcohol Metabolism

Around 5% of the ethanol is absorbed and metabolised by the gastric mucosal cells of the upper gastrointestinal tract. Due to the water soluble and lipid soluble nature of ethanol, it is absorbed readily from the intestine by passive diffusion. Most of the ethanol (85-98%) in the blood is metabolised by the liver. There are 2 major pathways of alcohol metabolism: the Alcohol Dehydrogenase pathway and the Microsomal Ethanol Oxidising System.

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The Alcohol Dehydrogenase pathway:

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This pathway is activated when there are low levels of alcohol present within the body. The reason for this is that the enzyme involved, the alcohol dehydrogenase (ADH), has a high affinity for the alcohol. Once in the liver, ethanol metabolism begins with its oxidation into acetaldehyde within the cytoplasm, a reaction which is catalysed by ADH. The acetaldehyde formed is very toxic and causes hangover-like symptoms including nausea, vomiting and headaches. The second reaction of this pathway involves the conversion of the acetaldehyde into acetate, an oxidation reaction which occurs in the mitochondria. This reaction is catalysed by the enzyme acetaldehyde dehydrogenase (ALDH). The acetate produced is then converted into Acetyl-CoA by the enzyme acetyl-CoA synthetase. This reaction also requires the input of an ATP molecule which produces a molecule of AMP and PPi. In the liver the enzymatic activity of acetyl-CoA synthetase is regulated by insulin levels. The Acetyl-CoA produced can then enter the pathways of fatty acid synthesis and cholesterol synthesis. Alternatively, acetate enters the blood stream and, upon arrival at muscle cells, is converted into acetyl-CoA which can then take part in the citric acid cycle.

 

Microsomal ethanol oxidising system

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The remainder of ethanol metabolism (around 10%) is accomplished by the Microsomal Ethanol Oxidising System (MEOS). This pathway utilises a cytochrome for the metabolism of the ethanol. As a consequence of the fact that this cytochrome has low affinity for the alcohol, the MEOS pathway is activated only when there is a high alcohol concentration. The function of this cytochrome is to oxidise the ethanol to acetaldehyde. The acetaldehyde which is formed is then metabolised in the same process as was described in the alcohol dehydrogenase pathway.

 

Sources:

Nelson, D. L., Cox, M. M., & Lehninger, A. L. (2013). Lehninger principles of biochemistry (6th ed.). New York, NY: Freeman.

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Figure 1 - Graphical representation of the alcohol dehydrogenase pathway primarily responsible for alcohol metabolism.

How does alcohol make you drunk?

Getting drunk occurs when you consume alcohol faster than you break it down. Common symptoms associated with being drunk include slurred speech, loss of coordination, falling, loss of inhibition, and passing out. All of these side effects are a result of our brain cells communicating at a slower rate. The initial euphoric effects of alcohol are a result of dopamine and serotonin being released in the brain. Dopamine is commonly referred to as the 'feel-good' neurotransmitter owing to its role in how we perceive pleasure, while serotonin is a neurotransmitter which is involved in feeling happy and calm. Alcohol also increases the effects of GABA, an inhibitory neurotransmitter. By increasing the effects of GABA, responses in the brain are impaired and, consequently, results in slurred speech. Our limbic system is involved in emotional responses, which is also slowed by alcohol, resulting in the loss of inhibition experienced while getting drunk. The cerebellum, the part of the brain that controls coordination, is very sensitive to alcohol. This is the reason why an inebriated person may stumble or have trouble walking straight. Alcohol may also dampen the reticular activating system, an area in the brainstem, which results in passing out or sleepiness. Alcohol also blocks vasopressin, a hormone that prevents our kidneys from eliminating too much fluid. This can increase the need to urinate and precipitate dehydration. A hangover occurs during and after the overconsumption of alcohol. The actual mechanism of what happens during a hangover is still not clear but is thought to be a result of the toxicity of acetaldehyde on the body, changes in electrolytes, dehydration, and low blood sugar. The most common symptoms during a hangover include headache, nausea, dizziness, and feeling sleepy/sluggish (Lynch, 2018).

 

Food in the stomach will absorb alcohol and, as a result, prevents it from entering the bloodstream immediately after consumption. This will delay and decrease the symptoms. Alcohol limits the production of ADH therefore, the kidneys will produce more urine upon alcohol consumption. Your liver can only oxidize one unit of alcohol per hour. So, the more you drink over a shorter period of time, the more drunk you will feel (Santos, 2020).

 

On average, it takes a person an hour to clear between 15mg and 18mg of alcohol per 100ml of blood. Fizzy alcohol will make you feel the effects of alcohol more quickly as the bubbles increase the pressure in your stomach, forcing alcohol into your bloodstream faster. Due to the higher concentration of muscle tissue in men when compared to women, females tend to require lower volumes of alcohol to get drunk. The reason for this is that, since muscles have more water than fat, alcohol will be diluted to a greater extent in a person with more muscle tissue. In addition to this reason, women also have lower levels of the ADH enzyme ("The science of alcohol", 2014).

 

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Alcohol Toxicity

The toxic effects caused by alcohol on organs and tissues in the body are mostly due to the presence of 4 substances: acetaldehyde, reactive oxygen, nitrogen species, and NAD+. Both acetaldehyde and oxidants are highly reactive molecules that can damage DNA, proteins, and lipids. This damage can lead to mitochondrial dysfunction, damage to signaling pathways and ion channels, as well as inflammation. Since alcohol can diffuse readily through cell membranes, it is able to affect most tissues in the body (Rusyn & Bataller, 2013).

 

How Alcohol is Involved in Fatty Liver Disease 

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Fatty liver disease is the first stage in alcohol-related liver disease which is caused by the excess intake of alcohol. The liver is responsible for many functions including the filtering of toxins from the blood, aiding digestion of food, regulating blood sugar and cholesterol levels, and also helps fight infections and diseases. Drinking large amounts of alcohol leads to the body producing too much fat or not being able to metabolise fat efficiently. This excess fat is stored in the liver cells where it accumulates and causes fatty liver disease. Excess fat in the liver can lead to inflammation which damages the cells and may also lead to scarring (“Everything You Need to Know About Fatty Liver”, 2019).

There are usually no visible symptoms associated with fatty liver disease but, in some cases, people may experience tiredness or pain on the upper right side of the abdomen. Alcoholic fatty liver disease can be treated and the effects reversed if the person stops consuming alcohol immediately and makes lifestyle changes such as eating a healthy diet of fruits, vegetables and whole grains whilst limiting the amount of salt and sugar, exercising regularly and getting vaccinated for hepatitis A and B as well as flu and pneumococcal disease (Monico, 2020).

 

See Figure 2

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Sources:

Rusyn, I., & Bataller, R. (2013). Reply to: “The autophagic response to alcohol toxicity: The missing layer”. Journal of Hepatology, 59(2), 399-400. doi:10.1016/j.jhep.2013.04.015

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Figure 2 - Infographic showing the toxic side effects associated with excessive alcohol intake.

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Alcohol in Disease

Alcohol and Cancer

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There is a link between alcohol and several types of cancers which occur in the oesophagus, breast, colon, and liver. The underlying mechanisms in which alcohol subsequently results in cancer are still not fully understood, however several plausible events have been described. For example; the genotoxic effect of acetaldehyde, induction of cytochrome P450 2E1 (CYP2E1) (conversion of various xenobiotics), nutritional deficiencies, interactions with retinoids, changes in the degree of methylation, immune surveillance, angiogenesis, and an increase in estrogen concentration.

 

Cardiovascular diseases

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Cardiovascular diseases (CVD) may result from excess alcohol intake as it leads to high blood pressure, heart failure or stroke. Excess alcohol also contributes to weight gain as it contains a high amount of calories which is harmful in the long term. Several factors influence the association between alcohol intake and CVD including genetics and biological variants however, alcohol consumption is the predominant factor. The increase in blood pressure results from several underlying mechanisms including impairment in cells that leads to the buildup of plaque in arteries, disruptions in arterial-vascular function, and hormonal imbalances that control the body’s fluid and blood pressure regulation. Alcohol intake also has a negative impact on the endothelial nitric oxide–generating system which acts as a homeostatic regulator of numerous essential cardiovascular functions. Therefore, endothelial dysfunction is an early indicator of blood vessel damage and atherosclerosis, as well as a strong prognostic factor for future CVD events.

 

Another effect of excess alcohol is vascular wall oxidative stress which specifically results in ethanol-induced hypertension. Oxidative stress is an imbalance between the production of free radicals and the disability to neutralize their harmful effect via antioxidants. Several studies using model organisms and humans has shown that there is a positive correlation between ethanol and the development of reactive oxygen species (ROS) which consequently leads to an increase in redox-signaling pathways and a decrease in protective antioxidant levels.

 

The myocardium is also affected by high alcohol intake. The ability of the heart to contract is weakened resulting in an irregular and often fast heart rate (arrhythmia) or, rarely, sudden cardiac death. This can lead to alcoholic cardiomyopathy (ACM) which is a heart-muscle disease found in individuals with a history of long-term heavy alcohol consumption.

 

See Figure 3.

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Alcohol Hepatitis

Alcohol Hepatitis is a type of disease that results from excessive alcohol intake. Large amounts of alcohol in the body can be toxic and so, once alcohol is ingested, the liver works to eliminate it via alcohol metabolism. During alcohol metabolism, reactive oxygen species are produced which, when present in a large amount, can lead to oxidative stress and, eventually, hepatocyte death by apoptosis. This process of apoptosis triggers the release of pro-inflammatory cytokines which up-regulate inflammatory reactions within the kidney. Therefore, the more alcohol ingested,  the more the inflammatory responses in the liver are triggered. The apoptosis of cells and inflammation result in scarring of the liver which starts to eventually replace healthy liver tissue resulting in alcohol hepatitis. More scarring may then result in liver cirrhosis which leads to alcohol liver disease.

Sources:

  • Lucey, M. R., Mathurin, P., & Morgan, T. R. (2009). Alcoholic hepatitis. New England Journal of Medicine, 360(26), 2758-2769. doi:10.1056/NEJMra0805786

 

Cirrhosis

Liver cirrhosis is late stage-scarring of the liver tissue that mainly progresses from alcohol hepatitis and liver fibrosis. Liver fibrosis is a process where the liver attempts to repair damaged tissue by replacing the tissue with collagenous scars. Excessive alcohol intake result in a lot of scarring of the liver tissue which may lead to blockage of the portal and atrial blood supply of the liver that lead to an inhibition of blood flow and ultimately the inhibition of exchange between sinusoids and liver cells. When the liver is in a stage of cirrhosis, it becomes swollen and less able to do its job and eventually results in portal-hypertension and alcohol liver disease.

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Alcoholic Pancreatitis

An increase in alcohol consumption can also result in a pancreatic disease called alcoholic pancreatitis. In fact, about 60-90% of patients with pancreatitis have a past history of excessive alcohol consumption. The proper pathophysiology of this disease is not really understood but many theories exist on how alcohol has a direct effect on pancreatitis. One of the theories is that alcohol causes digestive enzymes inside the pancreas to start self-digesting it. Alcohol allows the activation of trypsinogen and other enzymes far before they should be activated which results in the auto-digestion of the pancreas. Alcohol also increases the viscosity of the secretions of the pancreas which can lead to scarring and ulceration of the pancreas due to the formation of protein plugs. Chronic alcoholic pancreatitis can be fatal as there is no actual treatment of the disease. So, in this case, prevention is better than the cure and should be avoided by limiting alcohol intake.

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Figure 3 - Infographic showing diseases resulting from excessive alcohol intake.

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