Alcohol flush reaction, also known as “Asian flush”, is a condition when a person develops flushing, redness, nausea and even tachycardia after alcohol consumption. It occurs in predominantly Asians and about 36% of East Asians including Japanese, Chinese and Koreans experience this condition. When alcohol is consumed, alcohol dehydrogenases metabolizes ethanol into acetaldehyde which is a toxic and carcinogenic agent. Then, aldehyde dehydrogenase 2(ALDH2) metabolizes acetaldehyde to acetate. In some East Asian populations, a lysine allele replaces the glutamate allele in position 487 in the enzyme ALDH2. Lys/Lys homozygotes has no ALDH2 activity whereas Lys/Glu heterozygotes has reduced ALDH2 activity (Brooks). Therefore, “Asian flush” is mostly due to an inherited deficiency in the enzyme ALDH2 since acetaldehyde isn’t metabolized and accumulates in the body (Brooks). It can be used as a biomarker or predictor for ALDH2 deficiency. People with ALDH2 deficiency experience higher amounts of DNA and chromosomal damage than people with fully active ALDH2. High amounts of acetaldehyde can be associated with higher cancer risk. Studies have shown that facial flushing due to the acetaldehyde was associated with higher cancer risk, such as squamous cell esophageal cancer especially in East Asian men (Zhang). Esophageal cancer is one of the deadliest cancers in the world so it is essential for doctors to be informed about this so they can question and screen patients about previous episodes of alcohol-induced flushing. It is important for ALDH2-deficient patients to be educated on limiting their alcohol consumption which can possibly decrease the risk of developing esophageal cancer.
References
Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med. 2009;6(3):e50. doi:10.1371/journal.pmed.1000050
Zhang J, Zhang S, Song Y, et al. Facial flushing after alcohol consumption and the risk of cancer: A meta-analysis. Medicine (Baltimore). 2017;96(13):e6506. doi:10.1097/MD.0000000000006506
Alcohol flush reaction, commonly known as "Asian flush" or "Asian glow," is a physiological response predominantly observed in individuals of East Asian descent, such as Japanese, Chinese, and Koreans. This reaction, characterized by facial flushing, hives, nausea, and other symptoms, occurs due to genetic variations that impair the efficient metabolism of alcohol. Unlike an allergy, alcohol flush reaction is classified as alcohol intolerance, stemming from deficiencies in enzymes responsible for processing alcohol in the body.
The key enzymes involved in alcohol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). ADH converts alcohol into acetaldehyde, a toxic compound, which is then further broken down into harmless molecules by ALDH. In individuals with alcohol flush reaction, particularly prevalent among East Asians, mutations in genes coding for ADH2 and ALDH2 enzymes lead to ineffective breakdown of acetaldehyde. This results in its accumulation, triggering histamine release and the characteristic facial flushing.
The ALDH2 gene, in particular, has variants that significantly impact alcohol metabolism. The most common variant among East Asians involves a substitution at position 487, where glutamate is replaced by lysine. Homozygosity for the inactive ALDH2 allele (Lys/Lys) completely eliminates ALDH2 enzyme activity, severely impairing alcohol breakdown. This inability to metabolize acetaldehyde efficiently not only causes acute alcohol flush but also increases the risk of certain cancers, notably esophageal squamous cell carcinoma, when alcohol consumption is involved.
Esophageal cancer is a particularly lethal form of cancer globally, with alarmingly low survival rates. Studies conducted in Japan and Taiwan consistently link the presence of low-activity ALDH2 heterozygosity (Lys/Glu) with a heightened risk of esophageal squamous cell carcinoma, especially in individuals who consume alcohol heavily. This association remains robust even after adjusting for alcohol intake levels, with odds ratios for cancer risk ranging from 3.7 to 18.1 in various case-control studies. Prospective investigations further affirm these findings, revealing a significantly elevated relative hazard ratio for upper aerodigestive tract cancers among individuals with low-activity ALDH2 variants who consume alcohol.
Interestingly, individuals with ALDH2 deficiency do not face an increased risk of esophageal cancer if they abstain from alcohol. This underscores the pivotal role of alcohol metabolism in the carcinogenic pathway influenced by ALDH2 status. Moreover, the degree of risk associated with ALDH2 deficiency varies across populations, influenced by the prevalence of alcohol consumption and other environmental factors.
In conclusion, while alcohol flush reaction itself is a benign yet uncomfortable response to alcohol consumption, it serves as a critical indicator of underlying genetic predispositions affecting alcohol metabolism. The heightened risk of esophageal cancer among individuals with ALDH2 deficiency highlights the complex interplay between genetic susceptibility and environmental factors like alcohol consumption. Further research is essential to elucidate these mechanisms fully and inform strategies for cancer prevention, particularly in vulnerable populations with genetic variants impacting alcohol metabolism.
Brooks, P. J., Enoch, M. A., Goldman, D., Li, T. K., & Yokoyama, A. (2009). The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS medicine, 6(3), e50. https://doi.org/10.1371/journal.pmed.1000050
Jeon, S., Kang, H., Cho, I. et al. The alcohol flushing response is associated with the risk of depression. Sci Rep 12, 12569 (2022). https://doi.org/10.1038/s41598-022-16276-2