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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] 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[edit] 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[edit]

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]

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[42]. While no direct cause for this has been documented, it may be the case that due to impaired liver function, ADH and ALDH function more poorly than they otherwise would. Chronic alcohol use is known to lead to liver pathologies, that being alcoholic liver disease, which leads to further liver diseases like FLD, steatosis, and cirrhosis.(source needed) Because liver enzyme function is based on the relative function of liver cells (hepatocytes) (source needed) it could be inferred that liver disease caused by chronic alcohol use leads to poor metabolism of alcohol overtime, due to improper function of enzymes that would otherwise process alcohol.

Epigenetics

Epigenetic factors play a significant role in the deficiency of aldehyde dehydrogenase 2 (ALDH2), which is a key enzyme in metabolizing alcohol[39]. This deficiency contributes to alcohol intolerance by preventing the effective breakdown of acetaldehyde, a toxic intermediate produced during alcohol metabolism[39]. One primary mechanism involves changes in DNA methylation at the ALDH2 gene's CpG sites, which can affect the enzyme’s activity[38]. Lower methylation levels at these specific sites are linked to reduced ALDH2 expression, worsening symptoms of alcohol intolerance, such as facial flushing, headaches, and rapid heartbeat[39]. These symptoms are more pronounced in individuals with the ALDH2*2 genetic variant, which further decreases the enzyme's effectiveness due to an intrinsic structural mutation as well[38]​. Chronic alcohol exposure itself can lead to epigenetic modifications that influence how genes involved in alcohol metabolism are expressed[39]. Research has shown that repeated alcohol intake can alter DNA methylation across various genes, including ALDH2[40]. These changes are associated with a progressive sensitivity to alcohol, which amplifies the effects of genetic predisposition to alcohol intolerance[40]. For individuals with ALDH2 deficiencies, such epigenetic modifications can further hinder the body’s capacity to metabolize acetaldehyde effectively, leading to more severe or frequent symptoms over time[40]​. Aside from DNA methylation, other epigenetic factors such as histone modifications and the expression of non-coding RNAs also contribute to ALDH2 regulation [38]. These changes can impact the chromatin structure around the ALDH2 gene, reducing its accessibility for transcription and thus decreasing enzyme production[38]. 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[edit]

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.[20] Exposure to DMF can also cause facial flushing and increased sensitivity to alcohol.[21][22] Cultural associations with alcohol consumption may influence the severity of symptoms in certain individuals. In Chinese culture, the general cultural norm is to drink in moderation whereas in Korea, young adults, especially men, are encouraged to drink heavily in social settings[41]. This cultural norm of excessive drinking has shown to increase the severity of symptoms in individuals experiencing alcohol intolerance[41].

Diagnosis[edit]

Ethanol patch test[edit]

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.[23] Difference from alcohol allergy[edit] Alcohol intolerance is not an allergy.[24] 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.[25] The increased accumulation of acetaldehyde in affected individuals due to deficient aldehyde dehydrogenase enzymes often leads to the characteristic symptom of having flushed skin.[25][26][27] 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.[28][29] Nausea is a symptom common to both alcohol intolerance and alcohol allergy.[26] Remarkably, inhaled isopropyl alcohol can be used to provide nausea and vomiting relief.[30] [31] 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)[38]. Individuals with ALDH2 deficiency cannot metabolize acetaldehyde, a toxic byproduct of alcohol metabolism, effectively. This leads to symptoms such as facial flushing, nausea, rapid heartbeat, and abdominal discomfort immediately after alcohol consumption [38]. In contrast, alcohol allergy involves the immune system mistakenly identifying alcohol or its components (like sulfites and histamines) as harmful, triggering an immune response [39]. This can result in symptoms such as hives, difficulty breathing, and in severe cases, anaphylaxis [39]. Both conditions can present symptoms such as gastrointestinal distress and flushing. However, the timing and severity of these symptoms differ [38][39]. 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 [39].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[edit]

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.[32] Reducing alcohol consumption lowers the risk for cancer and other serious diseases.[33][34][35]

See also[edit]

• Alcohol tolerance
• Disulfiram-alcohol reaction
• Disulfiram-like drug
• Alcoholic liver disease

References[edit]

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