Alcohol Flush Reaction

 Alcohol Flush Reaction

by Hoi Kiu Wong

Image is a screenshot from ‘Asian Flush, explained’ by Vox 

https://www.youtube.com/watch?v=G6717bNakuA

INTRODUCTION 

2021 has arrived! Did you celebrate with your friends or family on New Years? If yes, did you experience the Alcohol Flush, also known as the ‘Asian Flush’? In this article, we will be looking into why the Alcohol Flush Reaction causes your face to go red and the chemistry behind it. 

ALCOHOL FLUSH REACTION 

Alcohol Flush Reaction (AFR) causes a person to develop a flush or erythema(1) on the face, neck, shoulders, or the whole body after drinking alcohol, as a result of an accumulation of acetaldehyde, a metabolic byproduct of the catabolic metabolism of alcohol. People who experience the so-called ‘Asian Flush’ or ‘Asian Glow’ have an aldehyde dehydrogenase 2 deficiency. This is common amongst East Asians; 30 to 50% of Chinese, Japanese and Koreans show these physiological responses to drinking alcohol which includes facial flushing, nausea, headaches and a fast heart rate (Tachycardia) [1] [2]. 

CAUSE OF ASIAN FLUSH 

Facial flushing is due to the dilation of blood vessels underneath your skin due to the accumulation of acetaldehyde. To understand this furter; for those unaffected by this condition, the liver breaks down alcohol like ethanol using its two main enzymes: Alcohol dehydrogenase (ADH), which first converts the ethanol into acetaldehyde (also known as ethanal) and aldehyde dehydrogenase (ALDH2), which converts acetaldehyde into acetic acid (also known as ethanoic acid) (See Fig. 1) [3]. 

Fig. 1 Metabolism of Ethanol into ethanal and then into ethanoic acid 

Note that acetaldehyde is broken down into acetate, an anion that turns into acetic acid when it gains a proton (Hydrogen ion) - which occurs when it reacts with water.

Image taken from https://en.wikipedia.org/wiki/Alcohol_flush_reaction [1] 

In the DNA of those who experience the ‘Asian flush’, there is a mutation in the gene that codes for the ALDH2 enzyme, making it inactive. Therefore, after drinking, the accumulated level of acetaldehyde is approximately six times higher than that of those who don’t have this condition. As Acetaldehyde is a formaldehyde, its toxicity triggers an immune response, which is why blood vessels dilate - making your face turn ‘tomato red’ [3]. 

In East Asian populations, there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys). The Glu allele (ALDH2*1) encodes a protein with normal catalytic activity; whereas, the Lys allele (ALDH2*2) encodes an inactive protein. Therefore, ALDH2 Lys/Lys homozygotes have no detectable ALDH2 activity, and ALDH2 Lys/Glu heterozygotes have less than half (reduction more than 100-fold) of the ALDH2 activity of Glu/Glu homozygotes (See Fig. 2) [3]. 

Fig. 2 Genotype frequency distribution of ALDH2 (rs671) 

Image taken from https://en.wikipedia.org/wiki/Alcohol_flush_reaction [1] 

User:was_a_bee - Frequency data is from Ensembl http://www.ensembl.org/Homo_sapiens/Variation/Population?v=rs671 ALFRED http://alfred.med.yale.edu/alfred/recordinfo.asp?condition=sites.site_uid=%27SI000734O World map is from File:Migration of Homa sapiens 01.svg. Beer icon is from File:Emoji u1f37a.svg.

Wondering what your ALDH2 genotype is? See Fig. 3. 

Fig. 3 Questionnaire to predict ALDH2 genotype 

Image taken from Gross, Eric R., et al. “A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant.” [5] 

HEALTH RISKS 

Facial flushing itself is not harmful; however, it may be a warning sign of other risks. 

In one 2013 study, it was shown that people who get flushed after drinking may have a higher chance of developing hypertension (high blood pressure), and there is also direct evidence showing that ALDH2-deficient individuals experience higher levels of acetaldehyde-related DNA damage than those with fully active ALDH2 when they drink the same amount of alcohol [4]. A study in Japanese alcoholics revealed that the amount of mutagenic acetaldehyde-derived DNA adducts in white blood cells was significantly higher in ALDH2-deficient heterozygotes than in individuals with active ALDH2 [2]. 

Therefore, it comes with no surprise that If you experience the ‘Asian Flush’ and drink heavily - you may be at higher risk of getting stomach or esophageal cancer or peptic ulcers. A study conducted in Japan, as well as other case control studies in Japan and Taiwan, have shown a strong link between the risk of esophageal squamous cell carcinoma and alcohol consumption in low-activity ALDH2 heterozygotes, with odds ratios (ORs) ranging from 3.7 to 18.1 after adjustment for alcohol consumption. For those that drink heavily, the ORs can go over 10 (See Fig. 3). Moreover, the results have shown that the relative risk of developing future upper aerodigestive tract (UADT, which includes the oral cavity, pharynx, larynx and esophagus) cancers in low activity ALDH2 heterozygotes is about 12 times higher than in individuals with active ALDH2. However, it is important to note that ALDH2 deficiency doesn’t influence esophageal cancer risk in non-drinkers, and the risk can also be affected by other factors; for instance, in rural parts of China, there is a high rate of esophageal cancer even though the drinking culture is not as strong as those in Japan and Taiwan, and results show a more modest positive association between low-activity ALDH2 heterozygous and esophageal cancer risk [2].

Fig. 3 Odds Ratios for Esophageal Cancer at different amounts of alcohol consumption for individuals with fully active ALDH2 and those that are ALDH2-deficient 

Image taken from Brooks, Philip J, et al. “The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption.” [2]

For those that are ALDH2 Lys/Glu heterozygotes, they experience a weaker manifestation of the flushing response due to their residual ALDH2 enzyme activity in their cells. Therefore, it is possible for them to develop tolerance to acetaldehyde. Due to habituation, the flushing response becomes weaker or comes much later at higher alcohol consumptions. Thus, this causes ALDH2 Lys/Glu heterozygotes to drink more - paradoxically causing them to be the group associated with the greatest risk of esophageal cancer from drinking alcohol, and not those who are ALDH2 Lys/Lys homozygotes [2]. Therefore, it is better to be aware of this as the body is reacting this way for a reason [3]. 

There are many more potential effects of the ALDH2 variant on human health - contributing towards the risk of psychological or cognitive disorders such as Alzheimer’s Disease, Endocrine diseases such as Diabetes, Cardiovascular diseases, Lung diseases, and more. There are studies that have shown clear associative risks with the ALDH2 variant for myocardial infarction (heart attack) and osteoporosis [5]. 

IS THERE A REMEDY OR ‘CURE’ TO GET RID OF THE ‘ASIAN FLUSH’ 

There are antihistamines or histamine blockers in the market e.g. Pepcid AC, Zantac and Zyrtec that have off-label uses; one of which is to ‘cure’ the ‘Asian Flush’ [6]. As histamines are the compounds involved in the inflammatory response; causing blood vessels dilate - inhibiting or blocking them can reduce the red glow. However, it is not recommended for people to take these medications in the hopes of reducing the redness as this practice is expected to increase the likelihood of developing esophageal cancer since one is more likely to drink more (no facial flushing to act as an indication to stop drinking) [2]. 

GLOSSARY

1. Erythema: Redness of the skin or mucous membranes, caused by hyperemia (increased blood flow) in superficial capillaries. It occurs with any skin injury, infection or inflammation. 

BIBLIOGRAPHY 

[1] “Alcohol Flush Reaction.” Wikipedia, Wikimedia Foundation, 21 Sept. 2020, en.wikipedia.org/wiki/Alcohol_flush_reaction. 

[2] Brooks, Philip J, et al. “The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption.” PLoS Medicine, vol. 6, no. 3, 2009, doi:10.1371/journal.pmed.1000050. 

[3] “Asian Flush (Alcohol Flush Reaction): Cures, Symptoms, Causes & Health Risks.” Alcohol Related-Health & Hydration Products, www.flyby.co/blogs/news/asian-flush. 

[4] Marks, Julie. “Does Your Face Turn Red When You Drink? Here’s Why.” Healthline, Healthline, 23 Jan. 2019, www.healthline.com/health/red-face-alcohol#is-it-dangerous. 

[5] Gross, Eric R., et al. “A Personalized Medicine Approach for Asian Americans with the Aldehyde Dehydrogenase 2*2 Variant.” Annual Review of Pharmacology and Toxicology, vol. 55, no. 1, 2015, pp. 107–127., doi:10.1146/annurev-pharmtox-010814-124915. 

[6] “Asian Flush Prevention: Best Way to Prevent Alcohol Flush Reaction.” Alcohol Related-Health & Hydration Products, www.flyby.co/blogs/news/asian-flush-prevention-best-way-to-prevent-alcohol-flush-reaction.