Alcohol intolerance

Last updated
Alcohol intolerance
Other namesAcute alcohol sensitivity
The Alcohol Flushing Response.png
Skin flushing, a common symptom of alcohol intolerance

Alcohol intolerance is due to a genetic polymorphism of the aldehyde dehydrogenase enzyme, which is responsible for the metabolism of acetaldehyde (produced from the metabolism of alcohol by alcohol dehydrogenase). [1] [2] This polymorphism is most often reported in patients of East Asian descent. [3] [4] [5] [6] Alcohol intolerance may also be an associated side effect of certain drugs such as disulfiram, metronidazole, or nilutamide. Skin flushing and nasal congestion are the most common symptoms of intolerance after alcohol ingestion. [5] [6] It may also be characterized as intolerance causing hangover symptoms similar to the "disulfiram-like reaction" of aldehyde dehydrogenase deficiency or chronic fatigue syndrome. [7] [8] [9] Severe pain after drinking alcohol may indicate a more serious underlying condition. [5] [10]

Contents

Drinking alcohol in addition to consuming calcium cyanamide can cause permanent or long-lasting intolerance (nitrolime disease), [11] [12] contributing (in conjunction with other substances) to the accumulation of harmful acetaldehyde in the body by inhibiting the acetaldehyde dehydrogenase enzyme.

Signs and symptoms

Individuals with alcohol intolerance will experience unpleasant reactions immediately after drinking alcohol. [13] [5] [6] Common signs and symptoms of alcohol intolerance include nasal congestion, skin flushing (redness), headaches, low blood pressure, nausea, and vomiting. [5] [6] [13]

Causes

Genetics

Alcohol metabolism Biotransformation pathway of ethanol (NIH NIAAA, 2007).png
Alcohol metabolism

ALDH1 is an isozyme of aldehyde dehydrogenase. A structural mutation in the gene of ALDH1, commonly found in East Asians, results in low levels of functional ALDH1 enzyme and thus, higher blood acetaldehyde levels. [14] [1] [2] Higher blood acetaldehyde levels have been associated with facial flushing caused by an increase in heart rate and blood flow to the face from vasodilation of the blood vessels. [1] [2] Individuals that have the ALDH2*2 allele, a variant that has a mutation when compared to the wild-type ALDH2 isozyme, are known to have higher blood acetaldehyde levels. [15] [16] [2] Individuals that have either mutation in the ALDH1 or ALDH2 genes may have slightly different blood acetaldehyde levels among others carrying a similar mutation and may experience varying degrees of alcohol intolerance symptoms. [17] [18] [19]

ALDH2 Molecular Structure of ALDH2.png
ALDH2
ALDH2 rs671 ALDH2 Varied SNP.png
ALDH2 rs671

ALDH2 pictured on the left, is an enzyme which breaks down acetaldehyde [20] [21] . Regions highlighted in yellow are structural and allow ALDH2 to fold properly [20] [21] . The region highlighted in red can vary between individuals (right) [22] . Individuals who have a G in their DNA will have normal folding and function of ALDH2 [20] . Individuals who have an A in their DNA will have a misfolded ALDH2 which will impair their ability to metabolize alcohol [22] . This is because the original amino acid (Glutamic acid) is positively charged and individuals with an A in their DNA will have an amino acid (Lysine) that is negatively charged causing repulsion and worse folding, inhibiting the enzyme's function [22] .

Epigenetics

Epigenetic factors, which are heritable changes in gene expression that do not involve alterations to the DNA sequence, can play a significant role in the deficiency of aldehyde dehydrogenase 2 (ALDH2), a key enzyme in metabolizing alcohol [23] . This deficiency contributes to alcohol intolerance by impairing the breakdown of acetaldehyde, a toxic intermediate produced during alcohol metabolism [23] . One primary mechanism involves DNA methylation, a chemical modification where methyl groups are added to DNA, often at CpG sites (regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide) [24] . Changes in DNA methylation at the ALDH2 gene's CpG sites can reduce enzyme activity [24] . Lower methylation at these sites reduces ALDH2 production, intensifying alcohol intolerance symptoms like facial flushing, headaches, and rapid heartbeat [23] .

Chronic alcohol exposure can itself cause epigenetic modifications, altering the expression of genes involved in alcohol metabolism, including ALDH2 [23] [25] . Research shows that repeated alcohol intake can change DNA methylation across various genes, contributing to progressive alcohol sensitivity and amplifying the effects of genetic predispositions to alcohol intolerance [25] . For individuals with ALDH2 deficiencies, these epigenetic changes can worsen the body’s ability to break down acetaldehyde, resulting in more frequent or severe symptoms over time [25] .

In addition to DNA methylation, other epigenetic mechanisms, such as histone modifications (chemical changes to the proteins that help package DNA) and non-coding RNAs (RNA molecules that regulate gene expression without encoding proteins), also influence ALDH2 regulation [24] . These factors can alter chromatin structure, the organization of DNA and proteins within the nucleus, reducing gene accessibility and decreasing enzyme production [24] . Combined with genetic predispositions, these epigenetic factors play a significant role in alcohol intolerance, as they contribute to inefficient alcohol metabolism and a buildup of acetaldehyde, resulting in the discomfort and adverse reactions experienced by affected individuals​.

Risk factors

Various genetic and environmental factors exist that can lead to an increased risk for developing alcohol intolerance. Individuals with two copies of the ALDH2*2 allele are known to have high blood acetaldehyde levels and experience “hangover” symptoms such as heart palpitations for longer durations, even with low alcohol consumption. [15] [16] [2] Individuals who work with DMF have shown a dose-related increase in alcohol intolerance complaints. [26] Exposure to DMF can also cause facial flushing and increased sensitivity to alcohol. [27] [28]

Acquired causes

Tolerance of alcohol varies with continued use, as individuals with alcohol dependence over a longer period are known to have lower tolerance to alcohol than those with a shorter period of dependence [29] . While no direct cause for this has been documented, one possibility is that due to impaired liver function, ADH and ALDH function poorer than they otherwise would. Chronic alcohol use is known to lead to liver pathologies, that being alcoholic liver disease, which leads to further liver conditions like FLD or steatosis, which is a buildup of fat in the liver, and cirrhosis, a buildup of scar tissue in the liver tissue [30] . Because liver enzyme function is based on the relative function of liver cells (hepatocytes) [31] liver disease caused by chronic alcohol use can lead to poor metabolism of alcohol overtime, due to improper function of enzymes that would otherwise process alcohol.

Diagnosis

Ethanol patch test

In an ethanol patch test, different concentrations of ethanol are applied onto lint pads and attached to the inner surface of the upper arm for several minutes. If skin redness occurs after 10–15 minutes, the individual is deemed to have a lack of ALDH1 associated with alcohol intolerance. [32]

Difference from alcohol allergy

Alcohol intolerance is not an allergy. [33] There are often misconceptions that alcohol intolerance and alcohol allergy are the same, but they are not. Alcohol intolerance is an inherited genetic disorder that impairs alcohol metabolism. [34] The increased accumulation of acetaldehyde in affected individuals due to deficient aldehyde dehydrogenase enzymes often leads to the characteristic symptom of having flushed skin. [34] [35] [36] On the other hand, the more uncommon alcohol allergy is an immune system reaction to alcohol (specifically ethanol) that causes symptoms such as rashes, difficulty breathing, and anaphylaxis in severe cases. [37] [38] Nausea is a symptom common to both alcohol intolerance and alcohol allergy. [35] Remarkably, inhaled isopropyl alcohol can be used to provide nausea and vomiting relief. [39] [40]

Alcohol intolerance and alcohol allergy, while often confused due to their overlapping symptoms, have distinct biological mechanisms. Alcohol intolerance is mainly due to genetic variations that affect the enzyme aldehyde dehydrogenase 2 (ALDH2) [24] . Individuals with ALDH2 deficiency cannot metabolize acetaldehyde, a toxic byproduct of alcohol metabolism, effectively. In contrast, alcohol allergy involves the immune system mistakenly identifying alcohol or its components, such as sulfites (preservatives commonly used in alcoholic beverages to prevent spoilage) and histamines (chemical compounds naturally produced during fermentation that can trigger inflammatory responses), as harmful, thereby triggering an immune response [23] . This can result in symptoms such as hives, difficulty breathing, and in severe cases, anaphylaxis [23] .

Both conditions can present symptoms such as gastrointestinal distress and flushing. However, the timing and severity of these symptoms differ [24] [23] . Alcohol intolerance typically causes immediate reactions after drinking, while allergic reactions can vary widely in onset and severity based on individual sensitivities to allergens present in alcoholic beverages [23] .

Understanding the distinctions between alcohol intolerance and alcohol allergy is crucial for proper alleviation of symptoms. Alcohol intolerance results from metabolic challenges related to enzyme function, while alcohol allergy involves the immune response. Recognizing these differences can help individuals avoid triggers and seek appropriate medical advice.

Management

Avoiding or restricting alcohol is the most straightforward way to prevent the symptoms of alcohol intolerance. [5] [6] [13] Tobacco use or exposure to secondhand smoke should be avoided, as smoking may increase levels of acetaldehyde. Certain medications may interact with alcohol and worsen symptoms. Antacid or antihistamines are used to reduce the symptoms of alcohol intolerance. However, these medications simply mask these symptoms. [41] Reducing alcohol consumption lowers the risk for cancer and other serious diseases. [42] [43] [44]

See also

Related Research Articles

Acetaldehyde is an organic chemical compound with the formula CH3CH=O, sometimes abbreviated as MeCH=O. It is a colorless liquid or gas, boiling near room temperature. It is one of the most important aldehydes, occurring widely in nature and being produced on a large scale in industry. Acetaldehyde occurs naturally in coffee, bread, and ripe fruit, and is produced by plants. It is also produced by the partial oxidation of ethanol by the liver enzyme alcohol dehydrogenase and is a contributing cause of hangover after alcohol consumption. Pathways of exposure include air, water, land, or groundwater, as well as drink and smoke. Consumption of disulfiram inhibits acetaldehyde dehydrogenase, the enzyme responsible for the metabolism of acetaldehyde, thereby causing it to build up in the body.

<span class="mw-page-title-main">Alcohol dehydrogenase</span> Group of dehydrogenase enzymes

Alcohol dehydrogenases (ADH) (EC 1.1.1.1) are a group of dehydrogenase enzymes that occur in many organisms and facilitate the interconversion between alcohols and aldehydes or ketones with the reduction of nicotinamide adenine dinucleotide (NAD+) to NADH. In humans and many other animals, they serve to break down alcohols that are otherwise toxic, and they also participate in the generation of useful aldehyde, ketone, or alcohol groups during the biosynthesis of various metabolites. In yeast, plants, and many bacteria, some alcohol dehydrogenases catalyze the opposite reaction as part of fermentation to ensure a constant supply of NAD+.

<span class="mw-page-title-main">Disulfiram</span> Chemical compound

Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol. Disulfiram works by inhibiting the enzyme aldehyde dehydrogenase, causing many of the effects of a hangover to be felt immediately following alcohol consumption. Disulfiram plus alcohol, even small amounts, produces flushing, throbbing in the head and neck, a throbbing headache, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, fast heart rate, low blood pressure, fainting, marked uneasiness, weakness, vertigo, blurred vision, and confusion. In severe reactions there may be respiratory depression, cardiovascular collapse, abnormal heart rhythms, heart attack, acute congestive heart failure, unconsciousness, convulsions, and death.

<span class="mw-page-title-main">Acetaldehyde dehydrogenase</span> Class of enzymes

Acetaldehyde dehydrogenases are dehydrogenase enzymes which catalyze the conversion of acetaldehyde into acetyl-CoA. This can be summarized as follows:

<span class="mw-page-title-main">Alcoholic polyneuropathy</span> Medical condition

Alcoholic polyneuropathy is a neurological disorder in which peripheral nerves throughout the body malfunction simultaneously. It is defined by axonal degeneration in neurons of both the sensory and motor systems and initially occurs at the distal ends of the longest axons in the body. This nerve damage causes an individual to experience pain and motor weakness, first in the feet and hands and then progressing centrally. Alcoholic polyneuropathy is caused primarily by chronic alcoholism; however, vitamin deficiencies are also known to contribute to its development. This disease typically occurs in chronic alcoholics who have some sort of nutritional deficiency. Treatment may involve nutritional supplementation, pain management, and abstaining from alcohol.

<span class="mw-page-title-main">Alcohol flush reaction</span> Effect of alcohol consumption on the human body

Alcohol flush reaction is a condition in which a person develops flushes or blotches associated with erythema on the face, neck, shoulders, ears, and in some cases, the entire body after consuming alcoholic beverages. The reaction is the result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol, and is caused by an aldehyde dehydrogenase 2 deficiency.

<span class="mw-page-title-main">Fomepizole</span> Medication

Fomepizole, also known as 4-methylpyrazole, is a medication used to treat methanol and ethylene glycol poisoning. It may be used alone or together with hemodialysis. It is given by injection into a vein.

<span class="mw-page-title-main">Alcohol tolerance</span> Bodily responses to the functional effects of ethanol in alcoholic beverages

Alcohol tolerance refers to the bodily responses to the functional effects of ethanol. This includes direct tolerance, speed of recovery from insobriety and resistance to the development of alcohol use disorder.

<span class="mw-page-title-main">Aldehyde dehydrogenase</span> Group of enzymes

Aldehyde dehydrogenases are a group of enzymes that catalyse the oxidation of aldehydes. They convert aldehydes to carboxylic acids. The oxygen comes from a water molecule. To date, nineteen ALDH genes have been identified within the human genome. These genes participate in a wide variety of biological processes including the detoxification of exogenously and endogenously generated aldehydes.

<span class="mw-page-title-main">ALDH2</span> Enzyme

Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. ALDH2 belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. ALDH2 has a low Km for acetaldehyde, and is localized in mitochondrial matrix. The other liver isozyme, ALDH1, localizes to the cytosol.

<span class="mw-page-title-main">Hangover</span> Discomfort following alcohol consumption

A hangover is the experience of various unpleasant physiological and psychological effects usually following the consumption of alcohol, such as wine, beer, and liquor. Hangovers can last for several hours or for more than 24 hours. Typical symptoms of a hangover may include headache, drowsiness, concentration problems, dry mouth, dizziness, fatigue, gastrointestinal distress, absence of hunger, light sensitivity, depression, sweating, hyper-excitability, irritability, and anxiety.

<span class="mw-page-title-main">Retinal dehydrogenase</span>

In enzymology, a retinal dehydrogenase, also known as retinaldehyde dehydrogenase (RALDH), catalyzes the chemical reaction converting retinal to retinoic acid. This enzyme belongs to the family of oxidoreductases, specifically the class acting on aldehyde or oxo- donor groups with NAD+ or NADP+ as acceptor groups, the systematic name being retinal:NAD+ oxidoreductase. This enzyme participates in retinol metabolism. The general scheme for the reaction catalyzed by this enzyme is:

<span class="mw-page-title-main">ADH1B</span> Protein-coding gene in the species Homo sapiens

Alcohol dehydrogenase 1B is an enzyme that in humans is encoded by the ADH1B gene.

<span class="mw-page-title-main">Short-term effects of alcohol consumption</span> Overview of the short-term effects of the consumption of alcoholic beverages

The short-term effects of alcohol consumption range from a decrease in anxiety and motor skills and euphoria at lower doses to intoxication (drunkenness), to stupor, unconsciousness, anterograde amnesia, and central nervous system depression at higher doses. Cell membranes are highly permeable to alcohol, so once it is in the bloodstream, it can diffuse into nearly every cell in the body.

<span class="mw-page-title-main">Coprine</span> Chemical compound

Coprine is a mycotoxin. It was first isolated from common inkcap. It occurs in mushrooms in the genera Coprinopsis. When combined with alcohol, it causes "Coprinus syndrome". It inhibits the enzyme aldehyde dehydrogenase, which is involved in the metabolism of alcohol. This inhibition leads to a buildup of acetaldehyde, causing an alcohol flush reaction. Because of this, the mushroom is commonly referred to as Tippler's Bane.

<span class="mw-page-title-main">ALDH1A1</span> Protein-coding gene in the species Homo sapiens

Aldehyde dehydrogenase 1 family, member A1, also known as ALDH1A1 or retinaldehyde dehydrogenase 1 (RALDH1), is an enzyme that is encoded by the ALDH1A1 gene.

Alcohol-induced respiratory reactions, also termed alcohol-induced asthma and alcohol-induced respiratory symptoms, are increasingly recognized as a pathological bronchoconstriction response to the consumption of alcohol that afflicts many people with a "classical" form of asthma, the airway constriction disease evoked by the inhalation of allergens. Alcohol-induced respiratory reactions reflect the operation of different and often racially related mechanisms that differ from those of classical, allergen-induced asthma.

<span class="mw-page-title-main">Disulfiram-like drug</span> Drug that causes an adverse reaction to alcohol

A disulfiram-like drug is a drug that causes an adverse reaction to alcohol leading to nausea, vomiting, flushing, dizziness, throbbing headache, chest and abdominal discomfort, and general hangover-like symptoms among others. These effects are caused by accumulation of acetaldehyde, a major but toxic metabolite of alcohol formed by the enzyme alcohol dehydrogenase. The reaction has been variously termed a disulfiram-like reaction, alcohol intolerance, and acetaldehyde syndrome.

<span class="mw-page-title-main">Alda-1</span> Organic compound

Alda-1 is an organic compound that enhances the enzymatic activity of human ALDH2. Alda-1 has been proposed as a potential treatment for the alcohol flush reaction experienced by people with genetically deficient ALDH2.

<span class="mw-page-title-main">Disulfiram-alcohol reaction</span> Medical condition

Disulfiram-alcohol reaction (DAR) is the effect of the interaction in the human body of alcohol drunk with disulfiram or some mushrooms. The DAR is key to disulfiram therapy that is widely used for alcohol-aversive treatment and management of other addictions. Once disulfiram-treated patients take alcohol, even in small doses, they experience strong unpleasant sensations.

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