Alcohol flush reaction

Alcohol flush reaction
Facial flushing. Before (left) and after (right) drinking alcohol. A 22-year-old ALDH2 heterozygote.
Classification and external resources
Specialty	Toxicology

The back of an Asian man experiencing alcohol flush

Alcohol flush reaction is a condition in which an individual develops flushes or blotches associated with erythema on the face, neck, shoulders, 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 acetaldehyde dehydrogenase deficiency.

This syndrome has been associated with an increased risk of esophageal cancer in those who drink.^[1] It has also been associated with lower than average rates of alcoholism, possibly due to its association with adverse effects after drinking alcohol.^[2]

Because of the association with Asian ancestry, alcohol flush reaction has also been referred to by such informal names as Asian flush syndrome, Asian flush, and Asian glow. Approximately 36% of East Asians (Japanese, Chinese, and Koreans) show a characteristic physiological response to drinking alcohol that includes facial flushing, nausea, and tachycardia.^[3]

Signs and symptoms

Individuals who experience the alcohol flushing reaction may be less prone to alcoholism. Disulfiram, a drug sometimes given as treatment for alcoholism, works by inhibiting acetaldehyde dehydrogenase, causing a five to tenfold increase in the concentration of acetaldehyde in the body. The resulting irritating flushing reaction tends to discourage affected individuals from drinking.^[4][5]

For measuring the level of flush reaction to alcohol, the most accurate method is to determine the level of acetaldehyde in the blood stream. This can be measured through both a breathalyzer test or a blood test.^[6] Additionally, measuring the amount of alcohol metabolizing enzymes alcohol dehydrogenases and aldehyde dehydrogenase through genetic testing can predict the amount of reaction that one would have. More crude measurements can be made through measuring the amount of redness in the face of an individual after consuming alcohol. Computer and phone applications can be used to standardize this measurement.

Other effects include "nausea, headache and general physical discomfort".^[7]

Many cases of alcohol-induced respiratory reactions, which involve rhinitis and worsening of asthma, develop within 1–60 minutes of drinking alcohol and are due to the same causes as flush reactions.^[8]

Causes

It is commonly thought that the flush reaction is caused by an inability to metabolize alcohol. On the contrary, around 80% of Asian people (less common in Thailand and India) have a variant of the gene coding for the enzyme alcohol dehydrogenase called ADH1B, whereas almost all Japanese, Chinese and Korean people have a variant of the gene called ADH1C,^[9] both resulting in an alcohol dehydrogenase enzyme that converts alcohol to toxic acetaldehyde at a much higher efficiency than other gene variants (40- to 100-fold in case of ADH1B).^[2]

In about 50% of Asians, the increased acetaldehyde accumulation is worsened by another gene variant, the mitochondrial ALDH2 allele, which results in a less functional acetaldehyde dehydrogenase enzyme, responsible for the breakdown of acetaldehyde.^[9] The result is that affected people may be better at metabolizing alcohol, often not feeling the alcohol "buzz" to the same extent as others, but show far more acetaldehyde-based side effects while drinking.

$\begin{smallmatrix} &\text{H}& &\text{H}& & & &\text{H}& &\text{H}& & &\text{H}& & & \\ & | & & | & &\mathsf{ADH} & & | & & | &\mathsf{ALDH} & & | & & & \\ \text{H}\,-\!&\text{C}&\!-\!&\text{C}&\!-\,\text{O}\,-\,\text{H}&\xrightarrow{\qquad}&\text{H}\,-\!&\text{C}&\!-\!&\text{C}&\xrightarrow{\qquad\ }&\text{H}\,-\!&\text{C}&\!-\!&\text{C}&\!-\,\text{O}\,-\,\text{H}\\ & | & & | & & & & | & & \| & & & | & & \| & \\ &\text{H}& &\text{H}& & & &\text{H}& &\text{O}& & &\text{H}& &\text{O}& \\ \end{smallmatrix}$

Metabolism of alcohol (ethanol) to acetaldehyde (ethanal) and then acetic acid (ethanoic acid)

Genetics

Genotype frequency distribution of ALDH2 (rs671).

Alcohol flush reaction is best known as a condition that is experienced by people of East Asian descent. According to the analysis by HapMap project, the rs671 allele of the ALDH2 responsible for the flush reaction is rare among Europeans and Africans. 30% to 50% of people of Chinese and Japanese ancestry have at least one ALDH2 allele.^[10] The rs671 form of ALDH2, which accounts for most incidents of alcohol flush reaction worldwide, is native to East Asia and most common in southeastern China. It most likely originated among Han Chinese in central China,^[11] and it appears to have been positively selected in the past. Another analysis correlates the rise and spread of rice cultivation in Southern China with the spread of the allele.^[2] The reasons for this positive selection aren't known, but it's been hypothesized that elevated concentrations of acetaldehyde may have conferred protection against certain parasitic infections, such as Entamoeba histolytica.^[12]

Pathophysiology

Those with facial flushing due to ALDH2 deficiency may be homozygotes, with two alleles of low activity, or heterozygotes, with one low-activity and one normal allele. Homozygotes for the trait find consumption of large amounts of alcohol to be so unpleasant that they are generally protected from esophageal cancer, but heterozygotes are able to continue drinking. However, an ALDH2-deficient drinker who drinks two beers per day has six to ten times the risk of developing esophageal cancer as a drinker not deficient in the enzyme.^[3][13]

The idea that acetaldehyde is the cause of the flush is also shown by the clinical use of disulfiram (Antabuse), which blocks the removal of acetaldehyde from the body via ALDH inhibition. The high acetaldehyde concentrations described share similarity to symptoms of the flush (flushing of the skin, accelerated heart rate, shortness of breath, throbbing headache, mental confusion and blurred vision).^[14]

Treatment

Since the mutation is a genetic issue, there is no cure for the flush reaction. Clinicians and the East Asian public generally know about the alcohol flushing response.^[3] Prevention would include not drinking alcohol.

Similar conditions

• Alcohol-induced respiratory reactions including rhinitis and exacerbations of asthma appear, in many cases, due to the direct actions of ethanol.
• Rosacea, also known as gin blossoms, is a chronic facial skin condition in which capillaries are excessively reactive, leading to redness from flushing or telangiectasia. Rosacea has been mistakenly attributed to alcoholism because of its similar appearance to the temporary flushing of the face that often accompanies the ingestion of alcohol.
• Degreaser's flush—a flushing condition arising from consuming alcohol shortly before or during inhalation of trichloroethylene (TCE), an organic solvent with suspected carcinogenic properties.
• Carcinoid syndrome – episodes of severe flushing precipitated by alcohol, stress and certain foods. May also be associated with diarrhea, wheezing and weight loss.
• Red ear syndrome,^[15] thought by many to be triggered by alcohol among other causes.

References

1. Alcohol Flush Signals Increased Cancer Risk among East Asians March 23, 2009 News Release - National Institutes of Health (NIH)
2. Yi Peng, Hong Shi, Xue-bin Qi, Chun-jie Xiao, Hua Zhong, Run-lin Z Ma, Bing Su (2010). "The ADH1B Arg47His polymorphism in East Asian populations and expansion of rice domestication in history". BMC Evolutionary Biology 10: 15. doi:10.1186/1471-2148-10-15. PMC 2823730. PMID 20089146.
3. Brooks PJ, 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. doi:10.1371/journal.pmed.1000050. PMC 2659709. PMID 19320537.
4. "Disulfiram". MedlinePlus Drug Information. Retrieved 15 November 2012.
5. Toxicity, Disulfiram at eMedicine
6. http://www.criticalimprov.com/index.php/surg/article/viewArticle/982/
7. http://dujs.dartmouth.edu/fall-2009/esophageal-cancer-and-the-‘asian-glow’
8. Adams, KE; Rans, TS (December 2013). "Adverse reactions to alcohol and alcoholic beverages.". Annals of Allergy, Asthma & Immunology 111 (6): 439–45. doi:10.1016/j.anai.2013.09.016. PMID 24267355.
9. Eng M. Y., Luczak S. E., Wall T. L. (2007.) "ALDH2, ADH1B, and ADH1C genotypes in Asians: a literature review", Alcohol Research Health, 30(1):22-7.
10. "Rs671".
11. Hui Li; et al. (2009). "Refined Geographic Distribution of the Oriental ALDH2*504Lys (nee 487Lys) Variant". Ann Hum Genet 73 (Pt 3): 335–45. doi:10.1111/j.1469-1809.2009.00517.x. PMC 2846302. PMID 19456322.
12. Oota; et al. (2004). "The evolution and population genetics of the ALDH2 locus: random genetic drift, selection, and low levels of recombination". Annals of Human Genetics.
13. Red Face May Signal Cancer Risk , New York Times, March 23, 2009
14. Wright C, Moore RD (1990). "Disulfiram treatment of alcoholism". Am. J. Med. 88 (6): 647–55. doi:10.1016/0002-9343(90)90534-K. PMID 2189310.
15. Boulton, P; Purdy, RA; Bosch, EP; Dodick, DW (2007). "Primary and secondary red ear syndrome: implications for treatment". Cephalalgia : an international journal of headache 27 (2): 107–10. doi:10.1111/j.1468-2982.2007.01270.x. PMID 17257229.

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