Asian Flush and Esophageal Cancer Linked

About 36% of East Asians (Japanese, Koreans and Chinese) have an enzyme deficiency that causes their skin to redden, or flush, when they drink alcohol.

Heavy alcohol consumption significantly raises the risk for esophageal cancer among such individuals, say scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and Japan’s Kurihama Alcohol Center. A paper(1) on the topic is in the March 24, 2009 issue of PLoS Medicine.

“Cancer of the esophagus is particularly deadly, with five-year survival rates ranging from 12 to 31 percent throughout the world. And we estimate that at least 540 million people have this alcohol-related increased risk for esophageal cancer,” notes first author Philip J. Brooks, Ph.D. “We hope that, by raising awareness of this important public health problem, affected individuals who drink will reduce their cancer risk by limiting their alcohol consumption.”

540 million people equates to about 8 percent of the world’s population.

Aldehyde Dehydrogenase 2

The deficient enzyme, known as aldehyde dehydrogenase 2 (ALDH2), has an essential role in metabolizing alcohol. When alcohol is drunk, the body first turns it into acetaldehyde, a chemical with similarities to formaldehyde, which causes DNA damage and other carcinogenic effects(2).

In the next step, ALDH2 is the main enzyme for breaking down acetaldehyde into acetate, a non-toxic metabolite in the body.

In East Asians, there are two variants of the ALDH2 gene; one produces an enzyme with normal activity, another produces an inactive form of the enzyme. When someone with the inactive variant drinks alcohol an acetaldehyde accumulation builds up in the body.

The result is symptoms like facial flushing, nausea, and rapid heartbeat (tachycardia). For individuals with two copies of the inactive variant, these symptoms are so extreme that they can drink very little alcohol.

Individuals with only one copy of the inactive variant, however, can develop a tolerance to the adverse effects of acetaldehyde, putting them at risk for alcohol-related esophageal cancer. In studies in Taiwan and Japan, up to 69% of excess risk for esophageal cancer can be attributed to drinking by the individuals with one copy of the inactive enzyme variant(3).

Cancer Risk Awareness

Epidemiological studies(4,5) by Akira Yokoyama and colleagues in Japan have demonstrated that individuals having one copy of the inactive variant are 6-10 times more likely to develop esophageal cancer than are individuals with the fully active ALDH2 enzyme who drink comparable amounts of alcohol.

These studies also note that people with the inactive variant drinking the equivalent of 33 or more U.S. standard drinks per week have a 89-fold increased risk of esophageal cancer compared to non-drinkers. Dr. Yokoyama is one of the co-authors of the new report.

“It is very important for clinicians who treat patients of East Asian descent to be aware of the risk of esophageal cancer from alcohol consumption in their patients who exhibit the alcohol flushing response, so they can counsel them about limiting their drinking,” according to NIAAA’s Kenneth R. Warren, Ph.D.

Researchers point out that many ALDH2-deficient university students will have their first experiences with heavy drinking in college. They also face peer pressures that will become more prevalent in their working like, particularly in Japan.

For that reason, it is important for university health care professionals to be aware of the relationship between ALDH2-deficiency, facial flushing, and alcohol-related cancer risk. Informing ALDH2-deficient young people of their risk of esophageal cancer from alcohol drinking is a valuable as well as cost-effective chance for cancer prevention.

Cigarette smoking raises the esophageal cancer risk further(6). In a synergistic way, cigarette smoking sharply increases acetaldehyde levels in saliva, and ALDH2-deficient individuals have a reduced capacity to clear salivary acetaldehyde.

Simply by asking about previous instances of facial flushing after drinking alcohol, clinicians can dependably establish whether a patient is at risk. Looked at from this perspective, the authors propose, the flushing response is a useful biomarker of genetic susceptibility to esophageal cancer risk from alcohol and a blessing in disguise.

References

1. 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 Med 6(3): e1000050. doi:10.1371/journal.pmed.1000050

2. Dellarco VL (1988) A mutagenicity assessment of acetaldehyde. Mutat Res 195: 1-20.

3. Foundation for Promotion of Cancer Research (2008) International comparisons of cancer
survival rates. Comparisons of 5-year relative survivals by site—6 Cancer Registries in Japan, the US SEER Program, and Eurocare-4. In: Cancer Statistics in Japan—2008. Tokyo: Foundation for Promotion of Cancer Research.

4. Yokoyama A, Muramatsu T, Ohmori T, Higuchi S, Hayashida M, et al. (1996) Esophageal cancer and aldehyde dehydrogenase-2 genotypes in Japanese

5. Yokoyama A, Omori T (2003) Genetic polymorphisms of alcohol and aldehyde dehydrogenases and risk for esophageal and head and neck cancers. Jpn J Clin Oncol 3 111-121

6. Lee CH, Wu DC, Lee JM, Wu IC, Goan YG, et al. (2007) Carcinogenetic impact of alcohol
intake on squamous cell carcinoma risk of the oesophagus in relation to tobacco smoking. Eur J Cancer 43: 1188-1199.

7. Ishikawa H, Ishikawa T, Yamamoto H, Fukao A, Yokoyama K (2007) Genotoxic effects of
alcohol in human peripheral lymphocytes modulated by ADH1B and ALDH2 gene polymorphisms. Mutat Res 615: 134-142.