Alcohol Flush Reaction

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

Individuals who consume alcohol may encounter an unpleasant occurrence known as alcohol flush reaction. The most prominent characteristic of this reaction is a “flushed” or red face, though other symptoms may manifest such as hives, nausea, low blood pressure, and an exacerbation of asthma or a migraine. More severely, alcohol flush reaction has been associated with increased risk of specific types of cancer. 

Alcohol flush reaction is categorized as an alcohol intolerance rather than an “alcohol allergy” and primarily stems from inherent genetic variations affecting certain enzymes, leading to less efficient alcohol metabolism. Normally, the enzyme alcohol dehydrogenase (ADH) converts alcohol into acetaldehyde, a toxic compound. Then, another enzyme, called aldehyde dehydrogenase (ALDH) metabolizes aldehyde into non-toxic molecules. In the case of alcohol flush reaction, acetaldehyde is not effectively metabolized, resulting in the induction of histamine and producing a flushed appearance and other undesirable symptoms. Genetic variants in the alcohol dehydrogenase gene (ADH18) and the aldehyde dehydrogenase gene (ALDH2) are recognized as the primary factors associated with elevated aldehyde levels resulting from modified alcohol metabolism. These variations are notably prevalent among individuals of East Asian descent. Nevertheless, individuals from other racial and ethnic backgrounds may also possess these genetic variations.

Approximately 36% of individuals of East Asian descent, including Japanese, Chinese and Koreans, exhibit a distinct physiological reaction to alcohol consumption, characterized by the aforementioned symptoms, known as “Asian flush” or “Asian glow.” This issue primarily arises from the inherited deficiencies in ALDH2 and ADH18 as aforementioned. Although there is a general awareness of the alcohol flushing response among the East Asian population, few are familiar with the growing body of evidence supporting the idea that ALDH-2 deficient individuals are at a significantly higher risk of esophageal cancer, specifically squamous cell carcinoma, due to alcohol intake. This is particularly concerning because esophageal cancer ranks amongst the most lethal cancers globally, with five-year survival rates of 15.6% in the United States, 12.3% in Europe and 31.6% in Japan. 

In the East Asian population, there are two primary variants of the ALDH2 gene, arising from the substitution of Glutamate (Glu) with Lysine (Lys) at position 487. The Glu allele normally encodes for a protein with normal catalytic function, while the Lys allele produces an inactive protein. Consequently, individuals homozygous for the Lys allele (Lys/Lys) exhibit no detectable ALDH2 activity. ALDH-2 deficient individuals who carry this mutation only metabolize alcohol into acetaldehyde, leading to its accumulation in the absence of ALDH2 activity. Due to the severity of this unpleasant reaction, ALDH2 Lys/Lys homozygotes are unable to tolerate substantial alcohol intake. Consequently, they are shielded from the heightened risk of esophageal cancer associated with alcohol consumption. ALDH2 Lys/Glu heterozygotes, on the other hand, undergo a milder form of the alcohol flushing reaction due to the presence of residual, although diminished, ALDH2 enzyme activity in their cells. Consequently, some individuals within this group can gradually develop tolerance to acetaldehyde and the flushing reaction, ultimately becoming habitual heavy drinkers. Paradoxically, it is the more prevalent, low-activity ALDH2 heterozygous genotype that poses the highest risk of esophageal cancer associated with alcohol consumption. 

Case-control investigations conducted in Japan and Taiwan consistently reveal a robust association between alcohol consumption and the risk of esophageal squamous cell carcinoma among individuals with low-activity ALDH2 heterozygosity. Following adjustments for alcohol consumption, odds ratios in these studies range from 3.7 to 18.1. Furthermore, most studies reveal odds ratios exceeding 10 for heightened risk amongst heterozygotes who engage in heavy drinking. Additionally, an independent meta-analysis has even shown an elevated risk in moderate-drinking individuals. Notably, in the Japanese and Taiwanese population, a substantial proportion (~58-69%) of the elevated risk of esophageal cancer is attributed to alcohol consumption by individuals with low-activity ALDH2 heterozygosity. Further supporting the findings in these case-control studies, prospective investigations involving alcoholics free of cancer have revealed that individuals with low-activity ALDH2 heterozygosity face a roughly 12-fold higher relative hazard ratio for future upper aerodigestive tract (UADT) cancers compared to those with active ALDH2 (encompassing the oral cavity, pharynx, larynx and esophagus). However, it is worth noting that ALDH2 deficiency does not affect the risk of esophageal cancer in those who abstain from alcohol consumption. Furthermore, the degree of esophageal cancer risk associated with ALDH2 deficiency varies depending on the relative significance of alcohol consumption versus other risk factors within a particular population. 

Resources: 

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

Alcohol flush reaction: Does drinking alcohol make your face red? National Institute on Alcohol Abuse and Alcoholism. September 2022. Accessed May 2, 2024. https://www.niaaa.nih.gov/publications/alcohol-flush-reaction-does-drinking-alcohol-make-your-face-red#:~:text=Some%20people%20who%20drink%20alcohol,or%20an%20episode%20of%20migraine. 

Alcohol flush syndrome, also known as Asian flush or Asian glow, is facial flushing seen after drinking alcohol. The flush reaction can extend to the neck, shoulders, and in rare cases, the entire body. Alcohol gets broken down in two steps. Upon consumption of alcohol, alcohol dehydrogenase (ADH) (an enzyme) converts alcohol into acetaldehyde, a toxic byproduct. Aldehyde dehydrogenase (ALDH2) (an enzyme) metabolizes acetaldehyde into acetate, a less toxic byproduct. In those with ALDH2 enzyme deficiency, acetaldehyde builds up due to the inability to break down into acetate. The body recognizes this as an allergic reaction and releases histamine. The histamine release induces increased heart rate, nausea, and flushing. The blood vessels dilate, causing superficial erythema that comes in blotches. To some, it may be a mere side effect of drinking, to others, they are self-conscious and it affects their social life.

There has been a lot of research done to prevent alcohol flush. Many over-the-counter products have been marketed, however, there are negative side effects if mixed with alcohol, contradicting the purpose of the product itself. Some at-home remedies consist of eating a heavy meal before drinking, to slow down the metabolism of alcohol, and slowing down acetaldehyde buildup. Another remedy is to simply drink slowly. Spacing out drinks can aid in allowing the body to flush out acetaldehyde, however, this may not be convenient depending on certain circumstances.

Flushing has been linked to hypertension and certain types of cancer such as esophageal cancer. The cancer, however, was not linked to women as it was to men. Aldehyde dehydrogenase 2 enzymatic deficiency is most common in East Asians, affecting nearly 560 million individuals. In a study conducted in 2013, the blood pressure of Korean men was observed among those who did and did not experience facial flush upon alcohol consumption. Upon completion of the study, it was determined that the men who drank and experienced flushing had a significantly higher risk of blood pressure when drinking four or more drinks per week. 

According to the American Cancer Society, acetaldehyde from alcohol consumption is a group 1 carcinogen. There is evidence to prove it can cause cancer in humans. Dr. Chen, the country director at Stanford Center for Asian Health Research and Education, conducted an ethanol patch test. Subjects were brought in, where a small amount of ethanol was applied to a bandaid and attached to their skin for 20 minutes. Blood vessels immediately dilated, causing a flushing reaction in the area. Another over-the-counter remedy commonly taken is an antihistamine. This may prevent skin flushing, however, acetaldehyde levels remain in the blood. The goal when drinking is usually to remove the flushing reaction. On the other hand, many have learned to embrace the temporary flush or have simply reduced alcohol intake which would benefit the individual.

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659709/

2. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10535860/

3. https://www.niaaa.nih.gov/publications/alcohol-flush-reaction-does-drinking-alcohol-make-your-face-red#:~:text=Some%20people%20who%20drink%20alcohol,or%20an%20episode%20of%20migraine.

Alcohol flush reaction, also known as Asian flush or Asian glow, is a physiological response to the consumption of alcohol, particularly found in 36% of individuals of East Asian descent. It is characterized by facial flushing, nausea, and tachycardia. This reaction is more common in people who have a genetic variation that affects the way their bodies metabolize alcohol, and it is not an allergy which is through a different mechanism. 

The key factor in alcohol flush reaction is the inefficient breakdown of acetaldehyde, a byproduct of alcohol metabolism. Acetaldehyde is normally further metabolized into a less harmful substance called acetate. However, some individuals, particularly those with an inherited deficiency in the enzyme ALDH2 gene, have a reduced ability to break down acetaldehyde. As a result, acetaldehyde accumulates in the body, leading to the symptoms of alcohol flush.  

Ethanol is first metabolized by alcohol dehydrogenase (ADH) into acetaldehyde. Acetaldehyde is then metabolized into acetate by ALDH2. “In East Asian populations there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys) [9]. The Glu allele (also designated ALDH2*1) encodes a protein with normal catalytic activity, whereas the Lys allele (ALDH2*2) encodes an inactive protein. As a result, Lys/Lys homozygotes have no detectable ALDH2 activity” (1).  Alcohol consumed by ALDH2-deficient individuals is metabolized to aldehyde which accumulates in the body, since it is not being converted to acetate, leading to facial flushing, nausea, and tachycardia. 

The facial flushing associated with alcohol flush reaction is often accompanied by other symptoms such as nausea, dizziness, and tachycardia as stated above too. While the reaction itself is not harmful, it may be uncomfortable for those who experience it. Individuals experiencing alcohol flush reaction may choose to limit their alcohol intake or avoid alcohol altogether to manage these symptoms. 

Certain online sources propose using antihistamines and specific over-the-counter medications to minimize or impede alcohol flushing. However, it's crucial to note that these medications do not neutralize the harmful effects of acetaldehyde. In reality, impeding alcohol flushing can increase the risk of cancer by facilitating greater alcohol consumption and subsequently higher production of acetaldehyde.

Clinicians can test ALDH2 deficiency through asking their East Asian patients if they experience flushing after drinking and if it was a tendency to always develop flushing after drinking. If the patient cannot remember, they can also do an ethanol patch test. “An ethanol patch test is performed as follows: 0.1 ml of 70% ethanol is pipetted onto a 15 × 15 mm lint pad fixed on an adhesive tape. The patch is attached to the inner surface of the upper arm for a 7-minute period and then removed. A patch area that shows erythema 10–15 minutes after removal is judged as positive” (1). 

Individuals who undergo the alcohol flush reaction and consume alcohol face an elevated risk of developing cancer, particularly esophageal and breast cancer. This heightened risk is attributed to the carcinogenic nature of acetaldehyde, a substance produced during the inefficient metabolism of alcohol in individuals experiencing the alcohol flush reaction.

References:

1. 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

2. https://www.niaaa.nih.gov/publications/alcohol-flush-reaction-does-drinking-alcohol-make-your-face-red#:~:text=Some%20people%20who%20drink%20alcohol,or%20an%20episode%20of%20migraine.

Alcohol Flush Reaction and the Risk of Esophageal Cancer

Alcohol flush reaction, also referred to as “asian glow” or “asian flush” is characterized by a pink to red flush of the body, particularly the face, neck, and chest, followed by nausea and tachycardia after ingestion of alcohol. This phenomenon is observed in approximately 36% of East Asians, which include Chinese, Japanese, and Korean individuals, thus explaining its race-associated nickname. Several studies have determined that populations who experience alcohol flush reaction are at an increased risk for the development of esophageal cancer.

The chemical composition of alcohol consists of ethanol and water. Upon alcohol ingestion, the ethanol group present in alcohol is oxidized via the enzyme, alcohol dehydrogenase, and to a lesser extent the cytochrome P450-dependent ethanol-oxidizing system, in the liver. The NAD+ cofactor also plays a role in this process since its responsibility is to accept the reducing equivalents (hydrogen and electrons) from the alcohol. The resulting metabolite is acetaldehyde and NADH. This alcohol dehydrogenase-catalyzed reaction is reversible. Further oxidative enzymatic processes by aldehyde dehydrogenase II (ALDH2) lead to the metabolite, acetate, which then exits the liver, circulates to peripheral tissues, and is activated to acetyl CoA (the acetyl CoA metabolite is also produced from the oxidative metabolism of carbohydrates, fats, and excess protein as well). This ALDH2 reaction is irreversible. Alcohol is hydrophilic based on its chemical constituents, and therefore, remains in body water until hepatic elimination proceeds. That being said, hepatic impairment, enzymatic deficiencies, sex, age, race, and use of drugs are all factors that may affect alcohol clearance given that 90% of alcohol metabolism is under the enzymatic activity of the liver.

It is found that individuals who experience alcohol flush reaction are deficient in the enzyme, aldehyde dehydrogenase II (ALDH2). Consequently, this results in accumulation of the metabolite, acetaldehyde, since acetaldehyde cannot be readily metabolized to acetate by ALDH2. Buildup of acetaldehyde is responsible for the reddening of facial features. To mitigate the flushing manifestations, especially in social settings, many of these individuals may decide to take H2 blockers before drinking as it can slow the breakdown of alcohol to acetaldehyde. This is a dangerous method since ethanol will eventually saturate the system despite delaying alcohol metabolism with an H2 blocker (i.e. Zantac, Tagamet, Pepcid). This can result in alcohol-induced poisoning. Taking antihistamines may mask severe alcohol-induced symptoms and lead to deadly situations. To continue, acetaldehyde is a mutagen and carcinogen that leads to DNA damage, thereby explaining the associated risk of esophageal cancer in ALDH2 deficient individuals. More specifically, east asians can express two main variants of ALDH2 that lead to poor alcohol metabolism: replacement of glutamate (Glu) at position 487 with lysine (Lys), resulting in Lys/Lys homozygous genotype, and Lys/Glu heterozygous genotype. The Glu allele (ALDH2*1) encodes normal catalytic activity. On the other hand, the Lys/Lys homozygotes (ALDH2*2) encodes inactive protein with no ALDH2 activity. Heterozygous Lys/Glu results in more than a 100-fold reduction in ALDH2 activity in comparison to those who have the Glu/Glu homozygous genotype. Facial flushing, nausea, and tachycardia then proceeds due to acetaldehyde accumulation in addition to histamine release. Those with Lys/Lys genotype have no ALDH2 activity and are incapable of consuming large amounts of alcohol, so they experience alcohol flushing more severely than those with the Lys/Glu genotype. Hence, this mechanism protects them against the risk of esophageal cancer. The manifestation of alcohol flushing is less severe in Lys/Glu genotype because ALDH2 activity is present despite low enzymatic levels. Due to this, these individuals may develop tolerance to acetaldehyde and the flushing response and can develop habitual heavy drinking habits. Given the genotypic differences regarding ALDH2 activity, populations that inherit the heterozygous Lys/Glu genotype are at a greater risk of esophageal cancer from heavy alcohol consumption.

According to case control studies conducted in asian populations in Japan and Taiwan, there exists a strong correlation between the risk of esophageal squamous cell carcinoma and alcohol consumption in ALDH2-deficient heterozygotes. Majority of the studies identified an odds ratio above 10 for increased risk of esophageal cancer in Lys/Glu heavy-drinkers. In other words, the odds of developing esophageal cancer in these particular individuals are 10 times more than those with the normal ALDH2 homozygous genotype Glu/Glu. In fact, the studies conducted in Japan and Taiwan quantified an excessive risk of 58%-69% for esophageal cancer in this genotypic characteristic. Moreover, prospective studies also indicated that ALDH2-deficient heterozygotes are 12 times more likely to develop future upper aerodigestive tract cancers (oral cavity, pharynx, larynx, and esophagus) than those with normal ALDH2 activity. Besides acetaldheyde’s role in facial flushing, its accumulation results in DNA and chromosomal damage, a primary mechanism of carcinogenic outcomes. The amount of mutagenic acetaldehyde-derived DNA adducts (a piece of DNA covalently bonded to acetaldehyde) and chromosomal damage in white blood cells were higher in ALDH2-deficient heterozygotes than in those with normal ALDH2 activity. This covalent chemical binding of acetaldehyde to DNA damages the DNA and results in abnormal replication and could start the mutation process. Without DNA repair, cancer is expected.

Given the data and mechanistic evidence, there exists a causal relationship between acetaldehyde and alcohol-associated esophageal cancer in ALDH2 deficient populations according to the 2007 International Agency for Research on Cancer Working Group. On the contrary, non-drinkers with ALDH2 deficiency do not influence esophageal cancer risk. Likewise, ALDH2-associated esophageal cancer risk also is influenced by other risk factors in the given population, such as age, sex, medication use, hepatic health, etc. To conclude, in order to raise awareness of ALDH2-associated esophageal cancer risk, prevent carcinogenic outcomes, and promote reduction of alcohol intake in affected groups, interprofessional healthcare interventions and patient education play a significant role.

References

Brooks, Philip J, et al. “The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption.” PLOS Medicine, 24 Mar. 2009, journals.plos.org/plosmedicine/article?id=10.1371%2Fjournal.pmed.1000050.

Cederbaum, Arthur I. “Alcohol Metabolism.” Clinics in Liver Disease, Nov. 2012, www.ncbi.nlm.nih.gov/pmc/articles/PMC3484320/.

Linan, Steve. “Antihistamines Prevent ‘Asian Flush’ - Alcohol-Induced Facial Redness - but Pose Risks.” USC News, 13 Sept. 2021, news.usc.edu/112489/antihistamines-prevent-asian-flush-the-red-face-some-people-get-from-alcohol-but-with-huge-risks/.

Paton, Alex. “Alcohol in the Body.” BMJ (Clinical Research Ed.), 8 Jan. 2005, www.ncbi.nlm.nih.gov/pmc/articles/PMC543875/#:~:text=More%20than%2090%25%20of%20alcohol,urine%2C%20sweat%2C%20or%20breath.

Rajalakshmi, T R, et al. “DNA Adducts-Chemical Addons.” Journal of Pharmacy & Bioallied Sciences, Apr. 2015, www.ncbi.nlm.nih.gov/pmc/articles/PMC4439668/.

Asian flush or asian glow is known to create a red face and neck when people drink alcohol, which also results in an increased heart rate, headaches, and nausea. Approximately 36% of East Asians have this characteristic physiological response to drinking alcohol. It’s predominantly due to an inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2).

Ethanol is primarily metabolized by alcohol hydrogenase (ADH) into acetaldehyde, which is subsequently metabolized to acetate, mainly by the enzyme ALDH2. East Asian populations have 2 main variants of ALDH2, resulting from replacement of glutamate (Glu) at position 487 with lysine (Lys). The Glu allele encodes a protein with normal catalytic activity, but the Lys allele encodes an inactive protein. Lys/Lys homozygotes have no detectable ALDH2 activity. Because the Lys allele acts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes have far less than half of the ALDH2 activity of Glu/Glu homozygotes, a reduction in ALDH2 activity of more than 100-fold.

The East Asian public generally knows about the alcohol flushing response, but few are aware of the evidence that ALDH2-deficient individuals are at a higher risk of esophageal cancer, specifically squamous cell carcinoma, from alcohol consumption than those with fully active ALDH2. Moderate alcohol consumption leads to an increased risk of esophageal cancer and reduction in alcohol drinking would translate to a substantial number of lives saved. The alcohol flushing response is a biomarker for ALDH2 deficiency and the intensity of the symptoms make people who have the response aware of it. Doctors should counsel patients with ALDH2 deficiency to reduce the risk of developing esophageal cancer.

Facial flushing response can be viewed as a cosmetic problem and antihistamines were used in an effort to blunt flushing while continuing to drink alcohol. Some people take an H2 blocker before they start drinking to slow the breakdown of alcohol to acetaldehyde. However, that is a dangerous practice because the person can end up consuming excess levels of alcohol because they become less aware of the behavioral effects of alcohol for a while, but the ethanol will eventually saturate the system and the higher levels will lead to increased behavioral changes in the person, including impaired judgment and alcohol poisoning.

There have been products in the market introduced to get rid of alcohol flush. A patch called glowless contains glutathione, which is the main ingredient to properly breakdown acetaldehyde, alpha lipoic acid, N-acetyl cysteine, vitamin C and B5, milk thistle extract, holy basil extract, quercetin, thiamine, and cosmoperine. The main focus is to accelerate the clearance of acetaldehyde by increasing ALDH activity. Typically, people use one patch for the entire night and it is recommended to keep the patch on until the following day so that it can keep working as they sleep. There are also a pill form under the company sunset containing quercetin, bromelain, dihydromyricetin, cysteine, L-theanine, and B vitamins to stop alcohol flushing before it can begin. Although there are solutions to asian flush, it should be recommended to reduce drinking, not only to avoid flushing, but also to decrease the risk of esophageal cancer.

References:

• Brooks, P. J., Enoch, M.-A., Goldman, D., Li, T.-K., & Yokoyama, A. (2009, March 24). The alcohol flushing response: An unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS medicine. Retrieved March 14, 2022, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659709/

• Ingredients. Glowless. (2021, December 29). Retrieved March 14, 2022, from https://glowless.co/ingredients/

• Asian flush pill: No glow pill. Sunset Alcohol Flush Support. (n.d.). Retrieved March 14, 2022, from https://getsunset.com/?matchtype=e&device=c&term=asian+flush+supplement&adgroup=79453421233&campaign=6499903568&gclid=Cj0KCQjwz7uRBhDRARIsAFqjulkRsAVTZeZzPaQNRNFBfW1GztaFbbax8IPBi4Pwa0VKO00wTWiE9SQaAiRSEALw_wcB

• Vuong, Z. (2021, September 13). Antihistamines prevent 'Asian flush' - alcohol-induced facial redness - but pose risks. USC News. Retrieved March 14, 2022, from https://news.usc.edu/112489/antihistamines-prevent-asian-flush-the-red-face-some-people-get-from-alcohol-but-with-huge-risks/

Alcohol Flush Reaction

Alcohol flush reaction is when the face and skin flushes red after drinking alcohol. This is an inherited metabolic disorder and is a type of reaction that indicates alcohol intolerance. When people drink alcohol, the body breaks down the alcohol into alcohol dehydrogenase (ADH), then it transforms into a toxic compound called acetaldehyde (CH3CHO). Then, aldehyde dehydrogenase 2 (ALDH2) breaks down acetaldehyde into acetate (CH3COO-). Acetate then breaks down into carbon dioxide and water.

However, not everybody’s body does this efficiently, resulting in an alcohol flush reaction. The body has difficulty metabolizing the acetaldehyde compound, so it accumulates in the body, leaving flushed skin, a rapid heartbeat, high blood pressure and other symptoms of alcohol flush

Approximately 8% of the world’s population has an alcohol flush reaction. About 36% of East Asians experience this type of flushing, hence the term “Asian flush” and “Asian glow”. These patients are recommended to avoid alcohol consumption because alcohol flush is associated with an increased risk of esophageal cancer in Asian men. Esophageal cancer is one of the deadliest cancers, with an average of five-year survival rate. But if drinking alcohol is unavoidable, limiting the frequency and amount of alcohol consumed, choosing alcohol with lower alcohol content, and staying hydrated may help minimize the alcohol flush reaction.

Alcohol flush reaction is not the same as alcohol allergy. Alcohol allergy is a rare immune system response to alcohol. The body treats the alcohol as an allergen or pollutant, and so can lead to anaphylaxis as the most severe side effect. Some other side effects of alcohol allergy are hives, eczema, or itchy skin, swollen face, throat or other areas of the body, difficulty breathing or congestion, nausea, vomiting, abdominal pain or diarrhea, lightheadedness, dizziness or loss of consciousness. Some people may also be allergic to other ingredients in alcohol such as grapes, wheat, rye, barley and yeast.

References

1. “Alcohol Flush Reaction (Causes, Symptoms & Treatment).” Alcohol Rehab Help, 14 Jan. 2022, https://alcoholrehabhelp.org/addiction/alcohol-flush-reaction/.

2. 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

Alcohol flushing syndrome occurs when people of asian ethnicity will consume alcohol, it is also referred to as “asian glow.” It is usually associated with high levels of acetaldehyde and can serve as a marker for a person’s overall sensitivity to alcohol. This syndrome is genetically linked through an inherited ALDH2 enzyme deficiency which will normally prevent toxic acetaldehyde accumulation during alcohol metabolism. In East Asian populations, alcohol flushing has been associated with being a phenotypic marker of AlDH2 rs671 polymorphism.

Alcohol flush reaction/facial flushing is commonly occurring in 36% of East Asians that includes Chinese, Japanese and Koreans. Other common physiologic responses include nausea and tachycardia. Alcohol flush reaction serves as a biomarker for ALDH2 deficiency. ALDH2 deficient individuals are at higher risk of esophageal cancer in particular squamous cell carcinoma due to moderate alcohol use. Typically ethanol is first metabolized by alcohol dehydrogenase (ADH) into acetaldehyde which is a mutagen that causes DNA damage and possibly cancer. Acetaldehyde is then metabolized to acetate by the enzyme ALDH2.

In East Asians there are two main variants of ALDH2 caused by displacement of glutamate (Glu) at position 487 with lysine (Lys). The Glu allele encodes a protein with normal catalytic activity, byt Lys encodes inactive protein resulting in Lys/Lys homozygotes with no detectable ALDH2 activity. Prospective studies in alcoholics without cancer, showed that the risk for developing upper aerodigestive tract (UADT) cancers (affecting the oral cavity, larynx, pharynx, and esophagus) in low-activity ALDH2 heterozygotes is 12 times higher than people with active ALDH2. ALDH2 deficiency does not however, influence risk of developing esophageal cancer in non-alcohol users.

Research is being done on evaluating the relationship between alcohol use and cardiovascular disease (CVD) by using alcohol flushing as an alternative phenotypic IV. In a formal MR analyses, there is an association between alcohol use and increased risk of hypertension studied in a Korean population. In this study, alcohol was associated with higher risk of hypertension and BP in men but there was no strong evidence for alcohol use affecting hypertension in women as predicted by alcohol flushing. In observational studies done in East Asian populations, people with inactive ALDH2 enzyme are more likely to experience facial flushing due to accumulation of aldehyde. The study reached a conclusion that there is a direct relationship between alcohol flushing and BP, as alcohol flushing will only influence BP after alcohol intake. As a result, individuals who are prone to facial flushing will reduce their alcohol intake thus reducing their risk for hypertension.

ALDH2 deficient patients should be counseled by pharmacists, physicians or other healthcare professionals to reduce their alcohol intake as much as possible. High-risk patients should be encouraged to perform endoscopic cancer screening.

1. Cho Y, Kwak S, Lewis SJ, et al. Exploring the utility of alcohol flushing as an instrumental variable for alcohol intake in Koreans. Sci Rep. 2018;8(1):458. Published 2018 Jan 11. doi:10.1038/s41598-017-18856-z

2. Brooks J. P., et al. The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption. Plos Medicine. Published 2009 March 24. Accessed 2021 May 28. https://doi.org/10.1371/journal.pmed.1000050

Alcohol-induced flushing is most prevalent in Asians and people of Mongoloid lineage due to aldehyde dehydrogenase gene polymorphisms that are common in these populations. After alcohol is ingested, it gets metabolized by alcohol dehydrogenase (ADH) into acetaldehyde in the liver. Aldehyde dehydrogenase (ALDH) is then responsible for further metabolizing the acetaldehyde into acetate. However, people with aldehyde dehydrogenase gene polymorphisms have a deficiency or inactive form of ALDH, causing acetaldehyde to accumulate. Acetaldehyde causes the flushing reaction by triggering catecholamine release from the adrenal medulla and sympathetic nervous system. The catecholamines cause direct vasodilation of the blood vessels, which leads to the flushing reaction and may be accompanied by an elevated heart rate, decreased blood pressure, dizziness, lightheadedness, nausea, vomiting, weakness, and anxiety. This flushing reaction can be intensified by medications such as sulfonylureas, disulfiram, metronidazole, ketoconazole, cephalosporins, and antimalarials. When these medications are taken concomitantly with alcohol, a disulfiram-like reaction will occur, which is typically characterized by flushing, nausea, vomiting, and hypotension. When these medications are dispensed, it is important for the pharmacist to counsel on avoiding alcohol to prevent the disulfiram-like reaction and further complications. For alcohol-induced flushing without concomitant medication use, there is no need for treatment as this condition is typically harmless and temporary. The only way to prevent it from happening is to avoid the ingestion of alcohol as the flushing can happen with any amount of alcohol, depending on the individual patient. There have been studies suggesting the use of oral antihistamines, aspirin, or topical brimonidine to prevent or minimize flushing, but there is not enough high quality data to support their use.

References:

1. Sadeghian A, Rouhana H, Oswald-Stumpf B, Boh E. Etiologies and management of cutaneous flushing: Nonmalignant causes. J Am Acad Dermatol. 2017;77(3):391-402. doi:10.1016/j.jaad.2016.12.031

2. Approach to flushing in adults. UpToDate. https://www-uptodate-com.jerome.stjohns.edu/contents/approach-to-flushing-in-adults?search=alcohol%20flushing&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1#H1. Updated March 6, 2020. Accessed March 26, 2021.

Alcohol flush is often referred to colloquially as Asian flush or Asian glow. This is because approximately 36% of East Asians (Japanese, Chinese, and Korean) show a characteristic physiological response to drinking alcohol that includes facial flushing, nausea, and tachycardia.1 This response is predominantly caused by an inherited deficiency in the aldehyde dehydrogenase 2 enzyme. The pubmed article linked as source 1 shows photos of a 22-year-old ALDH2 heterozygote before and after drinking alcohol. The study collects data on the increased risk for esophageal cancer for ALDH2-deficient patients. Doctors can ask patients simple screening questions to identify those who experience the condition in correlation to the experiences they have when consuming alcohol. In other words, the alcohol flush response is a biomarker for ALDH2 deficiency and increased risk for esophageal cancer.

Although most people who experience alcohol flush syndrome are East Asians, anyone can be affected if they cannot properly breakdown alcohol. When we consume alcohol, which is ethanol, an enzyme called alcohol dehydrogenase breaks it down to acetaldehyde. Then another enzyme called aldehyde dehydrogenase breaks down acetaldehyde into acetic acid. Acetic acid has a similar chemical structure to vinegar, which the body is able to dispose of through the liver, kidneys, and lungs. Patients who experience alcohol flush syndrome lack the aldehyde dehydrogenase enzyme so that acetaldehyde cannot be broken down. The accumulation of acetaldehyde is toxic and causes the common symptoms of dilated blood capillaries leading to redness, increased heart rate, headache, and nausea. As a pharmacist, we should advise patients to be cautious of the amount of alcohol consumption as a general health statement but also to reduce the discomfort that comes with alcohol flush syndrome and possible long-term effects of esophageal cancer. The effects of alcohol will vary from person to person so it is difficult to say how much is too much. Some people cope temporarily by taking Pepcid. Although this does not decrease the possible long-term effects of alcohol consumption, it is equivalent to slapping on a band-aid. Pepcid blocks histamine receptors in order to reduce flushing. Alcohol will still increase stomach acidity and the lack of redness takes away the hint from your body that you should stop drinking.

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2659709/

2. https://www.ahealthiermichigan.org/2018/10/23/what-exactly-is-alcohol-flush-syndrome/

3. https://atlasbiomed.com/blog/alcohol-intolerance-guide/

4. https://omecare.co/resources/blog/alcohol-flush-a-healthy-glow-or-health-concern/

Facial flushing in response to alcohol consumption occurs in about 36% of East Asian populations. Inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2) can cause side effects of facial flushing, nausea, and tachycardia. This enzyme plays a key role in breaking down alcohol for it to be excreted from the body. Asian flushing is sometimes joked as many are unaware of the correlation between ALDH2 deficiency and the increased risk of esophageal cancer, specifically squamous cell carcinoma. Esophageal cancer is one of the deadliest cancers in the world, so education plays a major role in increasing awareness among East Asian populations.

Due to the intensity of facial flushing, doctors simply need to ask their patients about past alcohol-induced flushing to determine if their patient has an ALDH2 deficiency. About 8% of the population worldwide are ALDH2- deficient, meaning about 540 million individuals. Even a small reduction of esophageal cancer Eastern Asians can substantially reduce the deaths of esophageal cancers around the world.

Ethanol is first metabolized by alcohol dehydrogenase into acetaldehyde, which is a mutagen and animal carcinogen that causes DNA damage and other cancer-promoting effects. Acetaldehyde is then metabolized by ALDH2 into acetate. In East Asians, there are two main variants of ALDH2. There is a replacement of glutamate at position 487 with lysine. This lysine encodes for the protein to be inactive resulting in no ALDH2 activity. In some East Asian populations, there are Lys/Glu heterozygotes and Lys/Lys homozygotes. Normally, ALDH2 would metabolize the acetaldehyde into Acetate which can be excreted from the body. When ALDH2 is inactive, there is an accumulation of acetaldehyde in the body which results in facial flushing, nausea, and tachycardia- the effects known as Asian flushing. In Lys/ Lys homozygotes, the reaction is so severe, patients usually stay clear of alcohol and therefore decrease the risk of developing esophageal cancer. In Lys/Glu heterozygotes, there is some metabolization of the acetaldehyde which results in less severe episodes of alcohol flushing. The tolerance of the less severe episodes builds and can become habitual heavy drinkers from the influence of social and cultural factors. As a consequence, the more common ALDH2 heterozygous genotype patients, have the greatest risk of esophageal cancer from alcohol consumptions.

Due to the histamine release from alcohol consumptions in patients with an ALDH2 deficiency, an off label use of antihistamines could help with the flushing associated with alcohol consumption in East Asian populations. In a study published in 2015, the effects of antihistamines in alcohol associated flushing were investigated. The control group received placebo tablets, while the investigational subjects received 50mg of diphenhydramine, an H1 receptor antagonist, and 300mg of cimetidine, an H2 receptor antagonist. In the antihistamine group, there was a significant reduction in skin flushing. There was also a decreased incidence of hypotension amongst the group. While the physical reaction was lessened, the risk of esophageal cancer was not diminished by the antihistamines. This is an important point to emphasize to patients to stress the importance of limiting alcohol consumption.

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

Miller NS, Goodwin DW, Jones FC, et al. Antihistamine blockade of alcohol-induced flushing in orientals. J Stud Alcohol. 1988;49(1):16-20. doi:10.15288/jsa.1988.49.16

Alcohol flush reaction is a known occurrence found to happen to approximately 36% of East Asians. It is known as a physiological response to drinking alcohol that leads to a reddish flush in the face. Upon estimation, there are around 540 million individuals with this condition in the world, which makes up about 8% of the total world population. Other symptoms that are most common in the alcohol flush reaction include nausea and tachycardia. One of the main reasons as to why the alcohol flush reaction happens is due to the deficiency in the enzyme aldehyde dehydrogenase 2, which is an inherited trait among Eastern Asians. Even though the symptoms of the alcohol flush reaction are not as debilitating and seem to only cause a few minor symptoms, there is alarming evidence that individuals deficient in this enzyme are linked to a much higher risk of developing esophageal cancer (specifically squamous cell carcinoma) compared to individuals that are not deficient. Esophageal cancer is one of the deadliest cancers worldwide with only a 15.6% five-year survival in the United States, and a 12.3% five-year survival rate in Europe.

The alcohol that is consumed by individuals with an ALDH2 deficiency is metabolized to acetaldehyde, which then accumulates in the body because it is unable to get broken down due to the lack of enzyme present. The unpleasant effects of this condition such as facial flushing, nausea, and tachycardia are due to the histamine release response from excess acetaldehyde accumulation. For this reason, some antihistamines such as diphenhydramine may be able to calm the flushing reaction that occurs after alcohol consumption. Ethanol can cause chromosomal damage with an ALDH2 deficiency and cause an increased amount of mutagenic acetaldehyde-derived DNA in white blood cells in those individuals that are deficient. Irregular cell growth in these mutagenic white blood cells can cause tumors to quickly spread throughout the esophageal area. However, when detected early, esophageal cancer can be treated by endoscopic mucosectomy, a non-invasive procedure that help cure the cancer. About 20% of esophageal cancer patients actually survive for three years after diagnosis, so prevention of the disease is of upmost importance.

Some ways to reduce the risk of developing esophageal cancer in patients that experience alcohol flush reaction is by simply talking to them about it. Most individuals that experience alcohol flush reaction are very aware they have it because of the intensity of the symptoms. Physicians can just ask patients about their previous episodes when consuming alcohol, and counsel their patients, explaining that reduced alcohol consumption equates to a reduce risk of the disease. In addition, patients who do experience the symptoms that match up to this condition should be regularly screened for endoscopic cancer. Even a small percentage of reduction in alcohol consumption would translate into a substantial amount of lives saved every year. The risk of developing esophageal cancer does increase when drinking a moderate amount of alcohol for these individuals, and this information should be expressed to patients as well as physicians.

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

There are also remedies that claim to reduce the flushing reaction that some people, mostly Asians, have when they ingest alcohol. One of the medications this study analyzes are antihistamines. In this study, they have two groups who will have alcohol flush reactions and they will attempt to compare the effect of antihistamines to this reaction. To start off the study, the flushing reaction was produced in the two study groups via the ingestion of a small amount of alcohol. Most subjects experienced a reddening of their skin along with hypotension, tachycardia and other symptoms such as dizziness, sleepiness, and nausea. Before the alcohol was given, half of the subjects were given 50 mg of diphenhydramine (H1 receptor antagonist) and 300 mg of cimetidine (H2 receptor antagonist). The second half acted as a control group and received a placebo instead of the antihistamines. The biggest difference noted between the antihistamine group and control group was in the skin flushing reaction. The experimental group who took the antihistamine showed a significant reduction in redness and flushing of the skin. Surprisingly, the antihistamines not only reduced the hotness but also neutralized the hypotension side effect of alcohol. Although this study does show a promising correlation between antihistamines and the reduced effects of ethanol flush reaction, it is impossible to say conclusively that it was due to the antihistamines without further testing and research.

This other study, however, claims that taking antihistamines with alcohol can actually increase accidents, because the concomitant use of a 1st generation sedating antihistamine and alcohol will have an increased drowsiness effect which can result in falls and other accidents. 2nd generation antihistamines, however, are less sedating which therefore could still produce the positive effects of an antihistamine with regards to alcohol flush reaction, without much of the negative drowsiness effect.

References

Miller NS, Goodwin DW, Jones FC, et al. Antihistamine blockade of alcohol-induced flushing in orientals. J Stud Alcohol. 1988;49(1):16-20.

Weathermon R, Crabb DW. Alcohol and medication interactions. Alcohol Res Health. 1999;23(1):40-54.