An Examination of the Genetic and Environmental Interactions Between the Alcohol Flushing Syndrome, the Hepatitis B Virus, and the Incidence of Hepatocellular Carcinomas

Introduction
Moderate to severe alcohol sensitivity is a well-known characteristic that has been observed in many Asiatic populations. The classic symptoms of alcohol sensitivity—facial flushing, elevated skin temperature, headache, peripheral vasodilation, tachycardia, and nausea and/or vomiting—are so closely associated with Asians in the broader culture that the flushing syndrome is colloquially known as the “Oriental Flush.” Researchers have discovered a correlation between individuals who exhibit the flushing syndrome (“flushers”) and excess acetaldehyde, which is a breakdown product of ethanol metabolism. However, until recently, the reason that such individuals have such abnormally high levels of acetaldehyde circulating in their bloodstreams has been murky, as well as why such a trait is selectively maintained in certain populations. While researchers now have a solid understanding of the biochemistry of the flushing reaction, the adaptive benefits of ALDH-mediated alcohol sensitivity remain much more ambiguous. While a variety of mechanisms have been proffered to explain the existence of the trait, one of the most convincing hypotheses postulates that the ALDH2*2 mutation confers protection against Hepatitis B-induced liver cancer, a disease that occurs at high rates in many Asian populations.

Discussion
Ethanol metabolism in humans is a multistage process that involves several different enzymes. In normal individuals, ethanol is first catalyzed into acetaldehyde by alcohol dehydrogenase (ADH), which is then converted to acetic acid by aldehyde dehydrogenase (ALDH) or cytochrome P-4502E1 (Iwahashi and Suwaki 1998; Mizoi et al. 1994). This underlying process initially led researchers to suspect that an atypical bioenzymatic pathway (or pathways) was probably responsible for alcohol sensitivity in Asians. Stamatoyannopoulos et al. (1975) were the first to propose a genetic basis for the observed difference by suggesting that the flushing syndrome was due to the presence of a high Km mutant form of the ADH enzyme. Given that acetaldehyde is known to cause symptoms of alcohol intoxication, it was hypothesized that individuals with the highly active form of ADH would quickly accumulate high levels of acetaldehyde in their bloodstreams, along with the associated flushing syndrome (Stamatoyannopoulos et al. 1975; Asmussen et al. 1948; von Wartburg et al. 1965).

Even so, while polymorphism of the ADH allele appeared to have a strong influence in the expression of the flushing syndrome, there remained lingering doubt that fast-acting ADH was solely responsible. Although the gene frequency of the atypical ADH allele in the Japanese population is quite high (90%), flushing symptoms occur in only about 50% of those same individuals (Goedde et al. 1979). The incongruity between high ADH frequencies and a middling rate of flushing responses led researchers to pursue other enzymatic pathways that might yield a statistically stronger correlation. Goedde et al. (1979) proposed a different hypothesis to explain high acetaldehyde blood levels in affected individuals, based on Greenfield and Pietruszko’s (1977) earlier discovery of two hepatic ALDH isozymes of differing bioactivity: a fast-migrating form (low Km for acetaldehyde, high Km for nicotinamide adenine dinucleotide, or NAD) and a slow-migrating form (high Km for acetaldehyde, low Km for NAD). Instead of rapid bioaccumulation of acetaldehyde due to abnormally rapid ethanol metabolism, Goedde et al. (1979) suggested that an ALDH isozyme with a low affinity for acetaldehyde could also lead to high levels in the bloodstream. Without the benefit of the active ALDH isozyme, acetaldehyde oxidation in affected individuals would be delayed by the sluggish characteristics of the slow-migrating mutant isozyme. This supposition has been largely confirmed by subsequent studies, which show no statistically significant difference in either the rate of ethanol metabolism between carriers of the normal and abnormal ADH allele, or in the rate of ethanol elimination between flushers and non-flushers (Edwards and Evans 1967; Mizoi et al. 1979).

The biochemistry of the alcohol flushing syndrome has largely been elucidated, yet its adaptive benefit remains unclear. Logic dictates that alcohol sensitivity must be conferring some level of fitness to those who are affected by it; no other mechanism can satisfactorily explain why it is being maintained at such high frequencies in the population. One avenue of research that has attracted a great deal of attention is the relationship between the flushing syndrome and lower-than-average rates of alcoholism. Alcoholism is a disease that is known to be much more prevalent among Caucasians than it is among Asians (Lin and Cheng 2002). This fact is reflected in the stark dichotomy of the racial distribution of ALDH2*2-mediated alcohol sensitivity: while the atypical ALDH allele is found in about 30 to 50% of individuals of Japanese, Chinese, Korean, Filipino, Thai, and Vietnamese descent, it occurs at extremely low frequencies in Caucasian populations (Goedde and Agarwal 1990; Lin and Cheng 2002). Furthermore, a substantial number of studies have demonstrated a strong correlation between alcohol sensitivity and a low incidence of alcoholism (e.g., Harada et al. 1982; Iwahashi and Suwaki 1998; Nakamura et al. 1996; Sládek 2003; Thomasson et al. 1991; Wall et al. 1992).

Taken together, these data suggest that individuals who are homozygous for the ALDH2*2 allele might be much less susceptible to alcoholism because the extremely unpleasant side effects of acetaldehydemia provide strong inhibitory action against the over-consumption of alcohol. In terms of enhancing fitness, however, it is less clear how evolutionarily advantageous a lower rate of alcoholism in Asian populations really is. While alcoholism is plainly responsible for the creation of an entire host of social and physiological pathologies (e.g., cirrhosis of the liver, accidental overdose, suicide/homicide, etc.), a strong argument can be made that these maladies do not fully manifest themselves until long after an individual has passed his or her prime reproductive years. In other words, alcoholics tend to produce offspring long before their disease matures to the point where it begins to seriously affect both their health and their reproductive success. Furthermore, multiple studies have demonstrated that moderate alcohol intake has a variety of health benefits that tend to decrease mortality (Doll et al. 1994; Thun et al. 1997). Therefore, while predisposition towards alcoholism is indisputably a maladaptive trait, protection against it cannot alone account for the lopsided frequency distribution of the ALDH2*2 allele. If this trait is capable of conferring such an enormous fitness advantage, it would become fixed very rapidly in the population, even where the allele occurs either at very low frequencies or is completely absent (e.g., Europe).

Furthermore, ALDH2*2-mediated protection against alcoholism is unlikely to bestow a significant reproductive advantage for another major reason. In addition to being far more toxic than the ethanol it is derived from, acetaldehyde is an established animal carcinogen that has been implicated in the development of a number of cancers, particularly of the head and neck. Epidemiological studies have repeatedly shown that consumption of alcoholic beverages among carriers of the ALDH2*2 is strongly correlated with squamous cell carcinomas of the mouth, pharynx, larynx, and esophagus, and that these carcinomas are often multiple in nature (Morita et al. 1994; Schwartz et al. 1994). This correlation has led researchers to speculate that the above-average rate of aerodigestive tract cancers seen in some Asian alcoholics may be due to chronic and systemic insult by high levels of acetaldehyde in the bloodstream. Furthermore, acetaldehyde has other pathways into the human body besides the consumption of alcoholic beverages: it is a component of tobacco smoke and automobile emissions, and it is widely used in the production of many industrial chemicals (Sládek 2003). Any adaptive benefits that can be attributed to protection against alcoholism will be negated to a greater or lesser extent by the fitness reduction of increased risk of malignant cancer.

One intriguing hypothesis that purports to explain the adaptive benefit of the ALDH2*2 allele has been proposed by Lin and Cheng (2002), who argue that the alcohol sensitivity trait provides an indirect selective advantage against the Hepatitis B virus (HBV). Liver cancer is the leading cause of death amongst Taiwanese males, and chronic liver disease and cirrhosis is the fifth leading cause of death in Taiwan; in fact, HBV-related hepatocellular carcinomas have been reported in individuals as young as six years of age (Lin and Cheng 2002). This fact has been ascribed to endemic HBV infection in the Taiwanese population, where most carriers are infected either perinatally, or by horizontal transmission during childhood. Interestingly, there appears to be a robust correlation between endemic HBV infection and high frequency of the ALDH2*2 allele; in other words, populations that exhibit the ALDH2*2 allele are all found within areas of high-HBV prevalence. Lin and Cheng (2002) report a strong geographical association between the incidence of HBV and the ALDH2*2 allele not only within China, but for the rest of the world as well.

Considering these findings, Lin and Cheng (2002) argue that the selective pressure exerted by liver disease on the Chinese population has made the ALDH2*2 allele an adaptive genetic trait in much the same way that sickle-cell disease (SCD) has become adaptive in malarial environments (see Livingstone 1958). This adaptation has arisen because HBV acts synergistically with other environmental factors (e.g., alcohol and tobacco consumption, aflatoxin exposure) to increase the incidence of liver diseases in the general population. In such an environment, HBV carriers who are genetically predisposed against excessive alcohol consumption will tend to have higher rates of survival than normal HBV carriers. This supposition has been confirmed by studies of European populations that do not possess the ALDH2*2 allele. Experiments show an extremely robust interaction between HBV positivity, heavy alcohol consumption, and elevated risk of hepatocellular carcinoma. A study conducted in Italy found that concurrent HBV infection and heavy alcohol consumption led to a much higher relative risk of developing liver cancer (64.7%), versus just 9.1% for concurrent HBV and lower alcohol use (Donato et al. 1997). Clearly, any mechanism that inhibits alcohol consumption in HBV-positive individuals will very likely result in a lower incidence of HBV-induced liver cancer.

Conclusion
While excessive consumption of alcohol is undeniably at the root of many social ills, the accumulating evidence suggests that a moderate level of alcohol intake actually confers a tangible health benefit, as reflected in lower mortality rates among light to moderate drinkers versus heavy drinkers and total abstainers. Such evidence has led researchers to argue that the ALDH2*2 allele is being maintained in Asian populations by balancing selection, primarily due to the fact that possession of the mutant allele appears to provide statistically significant protection against the development of hepatocellular carcinoma. The trait appears at very high frequencies in regions where HBV is endemic, and is rare or absent where virus activity is muted. Although more research must be carried out in order to confirm this conjecture, recent data support the notion that the increased frequency of the ALDH2*2 allele in Asians is attributable to enhanced protection against highly lethal malignant liver cancer.

References Cited
Asmussen, E., J. Hald, and V. Larsen. 1948. The pharmacological action of acetaldehyde on the human organism. Acta Pharmacological Toxicology 4, pp. 311–320.
Doll, R., R. Peto, E. Hall, K. Wheatly, and R. Gray. 1994. Mortality in relation to consumption of alcohol: 13 years’ observations on male British doctors. British Medical Journal 3309, pp. 911–918.
Donato F., A. Tagger, R. Chiesa, M. Ribero, V. Tomasoni, M. Fasola, U. Gelatti, G. Portera, P. Boffetta, and G. Nardi. 1997. Hepatitis B and C virus infection, alcohol drinking, and hepatocellular carcinoma: a case-control study in Italy. Hepatology 26, pp. 579–584.
Edwards, J. A., and D. A. P. Evans. 1967. Ethanol metabolism in subjects possessing typical and atypical liver alcohol dehydrogenase. Clinical Pharmacology and Therapeutics 8, pp. 824–829.
Goedde, H. W., S. Harada, and D. P. Agarwal. 1979. Racial differences in alcohol sensitivity: a new hypothesis. Human Genetics 51, 331–334.
Greenfield, N. J., and R. Pietruszko. 1977. Two aldehyde dehydrogenases from human liver: isolation via affinity chromatography and characterization of the isozymes. Biochimica et Biophysica Acta 483, pp. 35–45.
Higuchi, S., S. Matsushita, T. Muramatsu, M. Murayama, and M. Hayashida. 1996. Alcohol and aldehyde dehydrogenase genotypes and drinking behavior in Japanese. Alcoholism: Clinical and Experimental Research 20, pp. 493–497.
Iwahashi, K. and H. Suwaki. 1998. Ethanol metabolism, toxicity and genetic polymorphism. Addiction Biology 3, pp. 249–259.
Lin, Y. P., and T. J. Cheng. Why can’t Chinese Han drink alcohol? Hepatitis B virus infection and the evolution of acetaldehyde dehydrogenase deficiency. Medical Hypotheses 59(2), pp. 503–507.
Livingstone, F. B. 1958. Anthropological implications of sickle cell gene distribution in West Africa. American Anthropologist 60, pp. 533–562.
Mizoi, Y., I. Ijiri, Y. Tatsuno, T. Kijima, S. Fujiwara, J. Adachi, and S. Hishida. 1979. Relationship between facial flushing and blood acetaldehyde levels after alcohol intake. Pharmacology, Biochemistry, and Behavior 10, pp. 303–311.
Mizoi, Y., K. Yamamoto, Y. Ueno, T. Fukunaga and S. Harada. 1994. Involvement of genetic polymorphism of alcohol and aldehyde dehydrogenases in individual variation of alcohol metabolism. Alcohol and Alcoholism 29, pp. 707–710.
Morita, M., H. Kuwano, S. Ohno et al. 1994. Multiple occurrence of carcinoma in the upper aerodigestive tract associated with esophageal cancer: reference to smoking, drinking and family history. International Journal of Cancer 58, pp. 207–210.
Nakamura, K., K. Iwanashi, Y. Matsuo, R. Miyatake, Y. Ichikawa, and H. Suwaki. 1996. Characteristics of Japanese alcoholics with the atypical aldehyde dehydrogenase 2*2.1: a comparison of the genotypes of ALDH2, ADH2, ADH3, and cytochrome P-4502E1 between alcoholics and nonalcoholics. Alcoholism: Clinical and Experimental Research 20, pp. 52–55.
Schwartz, L. H., M. Ozsahin, Z. G. Zhang et al. 1994. Synchronous and metachronous head and neck carcinomas. Cancer 74, pp. 1933–1938.
Sládek, Norman E. 2003. Human aldehyde dehydrogenases: Potential pathological, pharmacological, and toxicological impact. Journal of Biochemical and Molecular Toxicology 17, pp. 7–23.
Stamatoyannopoulos, G., S. H. Chen, and F. Fukui. 1975. Liver alcohol dehydrogenase in Japanese: high population frequency of atypical form and its possible role in alcohol sensitivity. American Journal of Human Genetics 27, pp. 789–796.
Thomasson, H. R., H. J. Edenberg, D. W. Crabb, X. L. Mai, R. E. Jerome, T. K. Li, S. P. Wang, Y. T. Lin, R. B. Lu, and S. J. Yin. 1991. Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. American Journal of Human Genetics 48, pp. 677–681.
Thun, M. J., R. Peto, A. D. Lopez, et al. 1997. Alcohol consumption and mortality among middle-aged and elderly US adults. New England Journal of Medicine 337, pp. 1705–1714.
Von Wartburg, J. P., J. Papenberg, and H. Aebi. 1965. An atypical human alcohol dehydrogenase. Canadian Journal of Biochemistry 43, pp. 889–898.
Wall, T. L., H. R. Thomasson, M. A. Schuckit, and C. L. Ehlers. 1992. Subjective feelings of alcohol intoxication in Asians with genetic variations of ALDH2 alleles. Alcohol and Alcoholism 16, pp. 991–995.
Yokoyama, A., H. Watanabe, H. Fukuda, T. Haneda, H. Kato, T. Yokoyama, T. Muramatsu, H. Igaki, and Y. Tachimori. 2002. Multiple cancers associated with esophageal and oropharyngolaryngeal squamous cell carcinoma and the aldehyde dehydrogenase-2 genotype in male Japanese drinkers. Cancer Epidemiology, Biomarkers and Prevention 11, pp. 895–900.
Yokoyama, A., T. Muramatsu, T. Omori, T. Yokoyama, S. Matsushita, S. Higuchi, K. Maruyama, and H. Ishii. 2001. Alcohol and aldehyde dehydrogenase gene polymorphisms and oropharyngolaryngeal, esophageal, and stomach cancers in Japanese alcoholics. Carcinogenesis 22, pp. 433–439.