Cindy Mui MD
Faculty Peer Reviewed
The alcohol flushing response is a physiologic response to ingestion of alcohol and is characterized by facial flushing, nausea, tachycardia, and hypotension, felt to be due to an inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2). It is experienced by one third of East Asians and is more commonly known as the “Asian glow” or the “Asian flush”(1). Although the alcohol flushing response is generally seen as cosmetic and even embarrassing on a night out, there is evidence that there may be an association between this response and an increased risk for development of esophageal cancer. Worldwide, esophageal cancer is one of the deadliest cancers, due, in part, to detection at an advanced stage. The five-year survival rates of esophageal cancer are 15.6% in the U.S., 12.3% in Europe, and 31.6% in Japan (2).
Ethanol is absorbed by the small intestine and metabolized mainly in the liver by alcohol dehydrogenases (ADH) to acetaldehyde. When alcohol intake is high, cytochrome P450 2E1 also metabolizes ethanol into acetaldehyde, producing reactive oxygen species (ROS) as a byproduct. Acetaldehyde is then converted into acetate by aldehyde dehydrogenases (ALDH) (3). The level of acetaldehyde produced during alcohol metabolism is therefore dependent on the delicate balance between consumption and metabolism rate, with elevated levels causing the aversive reaction, seen with the flushing response. This aversive reaction serves as a counterbalance against the euphoric reactions that may reinforce alcohol’s use (4).
There are many studies examining the role of genetic polymorphisms in the risk of alcohol related cancers but the best studied are polymorphisms of the ALDH2 gene. In East Asians, up to 40% have a polymorphism of ALDH2 in which glutamate is substituted for lysine at position 487. Individuals with the Glu allele (ALDH2*1/*1) have normal enzymatic activity whereas individuals who are homozygous for the Lys allele (ALDH2*2/*2) do not have any ALDH2 activity at all and accumulate acetaldehyde during alcohol consumption and therefore develop the flushing response. ALDH2*1/*2 heterozygotes have approximately 6% residual activity and therefore, have a less severe flushing response. As a result, some heterozygotes are able to develop tolerance to the flushing response and have a greater risk of becoming habitual heavy drinkers (5). Ethanol is carcinogenic to human beings, the mechanism of which is closely related to its metabolism. While the accumulation of ROS causes DNA damage and may play a role in carcinogenesis, acetaldehyde, itself, is thought to be the main carcinogen in the upper and lower gastrointestinal tract. Acetaldehyde interferes with DNA synthesis and DNA repair and higher levels of acetaldehyde-related DNA and chromosomal damage are seen in ALDH2 deficient individuals compared to normals with consumption of similar amounts of alcohol (3, 6).
Ethanol —–ADH——–→ acetaldehyde —–ALDH2*1/*1————-→ acetate
Ethanol —–ADH——–→ ↑ acetaldehyde —ALDH2*1/*2 or *2/*2——–→ ↓ acetate
Several studies have shown a significantly increased risk for esophageal cancer in Asians who drink alcohol with the ALDH2*1/*2 genotype compared to those who have the ALDH2*1/*1 or *2/*2 genotype, mainly from increased levels of acetaldehyde. A meta-analysis by Lewis, et al. of 7 case-control studies involving 905 patients showed that the risk of esophageal cancer was reduced in ALDH2 deficient homozygotes [odds ratio (OR) 0.36, 95% confidence interval (95% CI) 0.16-0.80] and increased in heterozygotes (OR 3.19, 95% CI 1.86-5.47) compared to *1/*1 homozygotes. This meta-analysis suggested that alcohol intake increases the risk of esophageal cancer, but those individuals without any ALDH2 activity are protected from esophageal cancer because they limit their alcohol consumption due to the unpleasant flushing response (7). Heterozygotic individuals with reduced activity of ALDH2 have an increased risk for esophageal cancer at all levels of alcohol consumption (low, moderate, and high) compared with those with normal ALDH2 activity as they do not experience significant alcohol aversion, yet produce higher levels of acetaldehyde (1).
Given the strong association between ALDH2 deficiency and the risk for esophageal cancer, the flushing response may be clinically useful to detect ALDH2 deficiency and thereby offer clinicians the opportunity to counsel patients about their increased risk of esophageal cancer with alcohol consumption. A questionnaire was developed in Japan that was shown to have 90% sensitivity, 88% specificity, 87% positive predictive value to detect ALDH2 deficiency. The questions asked were:
1. Do you have a tendency to flush in the face immediately after drinking a glass (180 ml) of beer?
2. Did you have a tendency to flush in the face immediately after drinking a glass of beer during the first to second year after you started drinking?
By answering yes to either question, the individual was considered to be ALDH2 deficient and could be counseled to reduce alcohol intake and possibly referred for endoscopic evaluation depending on the clinical scenario (8). This questionnaire may be most useful to identify heterozygotes who may have developed tolerance and have used home remedies such as antihistamines to counteract the flushing response in order to consume alcohol without aversion. Despite the fact that this questionnaire was developed in Japan and has not been validated in Asian populations in the U.S., the low five-year survival rates of esophageal cancer make this questionnaire an intriguing and easy way to screen patients and offer a basis for counseling to reduce risk. The Asian glow may not be just a nuisance but rather one of nature’s ways of protecting against cancer.
Reviewed by Michael Poles MD, Associate Editor, Clinical Correlations, Assistant Professor of Medicine, NYU Division of Gastroenterology
References
1. Brooks PJ, Enoch M-A, Goldman D, et al. The alcohol flushing response: An unrecognized risk factor for esophageal cancer from alcohol consumption. PloS Med 2009;6(3):e1000050.doi:10.1371/journal.pmed.1000050
2. Umar SB, Fleischer DE. Esophageal cancer: Epidemiology, pathogenesis and prevention. Nat Clin Pract Gastroenterol Hepatol 2008;5:517-26.
3. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007;7:599-612.
4. Eriksson CJ. The role of acetaldehyde in the actions of alcohol (update 2000). Alcohol Clin Exp Res 2001;25(5):15S-32S.
5. Yokoyama A, Omori T. Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. Jpn J Clin Oncol 2003;33(3):111-21.
6. Baan R, Straif K, Grosse Y, et al. Carcinogenicity of alcoholic beverages. Lancet Oncol 2007;8:292-3.
7. Lewis SJ, Smith GD. Alcohol, ALDH2, and esophageal cancer: A meta-analysis which illustrates the potentials and limitations of a mendelian randomization approach. Cancer Epidemiol Biomarkers Prev 2005;14(8):1967-71.
8. Yokoyama T, Yokoyama A, Kato H, et al. Alcohol flushing, alcohol and aldehyde dehydrogenase genotypes and risk for esophageal squamous cell carcinoma in Japanese men. Cancer Epidemiol Biomarkers Prev 2003;12:1227-33.