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The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption

The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption

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The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption
The Alcohol Flushing Response: An Unrecognized Risk Factor for Esophageal Cancer from Alcohol Consumption

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PLoS Medicine | www.plosmedicine.org0258March 2009 | Volume 6 | Issue 3 | e1000050
Research in Translation
The Alcohol Flushing Response:An Unrecognized Risk Factor for EsophagealCancer from Alcohol Consumption
Philip J. Brooks*, Mary-Anne Enoch, David Goldman, Ting-Kai Li, Akira Yokoyama*
 A
pproximately 36% of East  Asians (Japanese, Chinese, andKoreans) show a characteristicphysiological response to drinkingalcohol that includes facial flushing(see Figure 1), nausea, and tachycardia[1] . This so-called alcohol flushingresponse (also known as “Asian flush”or “Asian glow”) is predominantly due to an inherited deficiency in theenzyme aldehyde dehydrogenase 2(ALDH2) [2]. Although cliniciansand the East Asian publicgenerally know about the alcohol flushingresponse (e.g., http://www.echeng.com/asianblush/), few are awareof the accumulating evidence that  ALDH2-deficient individuals are at much higher risk of esophageal cancer(specifically squamous cell carcinoma)from alcohol consumption thanindividuals with fully active ALDH2.This is particularly unfortunate asesophageal cancer is one of thedeadliest cancers worldwide [3], withfive-year survival rates of 15.6% in theUnited States, 12.3% in Europe, and31.6% in Japan [4].Our goal in writing this article isto inform doctors firstly that their ALDH2-deficient patients have anincreased risk for esophageal cancerif they drink moderate amounts of alcohol, and secondly that the alcoholflushing response is a biomarkerfor ALDH2 deficiency. Because of the intensity of the symptoms, most people who have the alcohol flushingresponse are aware of it. Thereforeclinicians can determine ALDH2deficiency simply by asking about previous episodes of alcohol-inducedflushing. As a result, ALDH2-deficient patients can then be counseled toreduce alcohol consumption, andhigh-risk patients can be assessed forendoscopic cancer screening. Based onthe sizes of the Japanese, Chinese, andKorean populations and the expectedfrequency of ALDH2-deficient individuals in each [1], we estimate that there are at least 540 million ALDH2-deficient individuals in the world,representing approximately 8% of thepopulation. In a population of this size,even a small reduction in the incidenceof esophageal cancer could result ina substantial reduction in esophagealcancer deaths worldwide.
A Primer on the Genetics of Alcohol Metabolism
Ethanol is first metabolized primarily by alcohol dehydrogenase (ADH) intoacetaldehyde (Figure 2), a mutagenand animal carcinogen that causesDNA damage and has other cancer-promoting effects [5–7]. Acetaldehydeis subsequently metabolized to acetate,mainly by the enzyme ALDH2 [8]. InEast Asian populations there are twomain variants of 
ALDH2 
, resultingfrom the replacement of glutamate(Glu) at position 487 with lysine (Lys)[9]. The Glu allele (also designated
ALDH2*1
) encodes a protein withnormal catalytic activity, whereasthe Lys allele (
ALDH2*2 
) encodesan inactive protein. As a result, Lys/Lys homozygotes have no detectable
Funding:
 The authors received no specific fundingfor this article.
Competing Interests:
 The authors have declaredthat no competing interests exist.
Citation:
BrooksPJ, Enoch M-A, Goldman D, Li T-K,Yokoyama A (2009)The alcohol flushing response:An unrecognized risk factor for esophageal cancerfrom alcohol consumption.PLoS Med 6(3): e1000050.doi:10.1371/journal.pmed.1000050 This is an open-access article distributed under theterms of the Creative Commons Public Domaindeclaration, which stipulates that, once placed in thepublic domain, this work may be freely reproduced,distributed, transmitted, modified, built upon, orotherwise used by anyone for any lawful purpose.
Abbreviations:
ADH, alcohol dehydrogenase;ALDH2, aldehyde dehydrogenase 2; Glu, glutamate;Lys, lysine; OR, odds ratio; UADT, upper aerodigestivetractPhilip J. Brooks, Mary-Anne Enoch, and DavidGoldman are in the Laboratory of Neurogenetics,National Institute on Alcohol Abuse and Alcoholism,National Institutes of Health, Rockville, Maryland,United States of America. Ting-Kai Li is the formerDirector of the National Institute on Alcohol Abuseand Alcoholism, National Institutes of Health. He isnow a Professor at the Duke–National University of Singapore Graduate Medical School, Durham, NorthCarolina, United States of America. Akira Yokoyamais Director of Clinical Research Unit, National HospitalOrganization Kurihama Alcoholism Center, Nobi,Yokosuka, Kanagawa, Japan. Philip J. Brooks andAkira Yokoyama were participants in the 2007International Agency for Research on Cancer WorkingGroup on alcoholic beverage consumption.* To whom correspondence should be addressed.E-mail: pjbrooks@mail.nih.gov; a_yokoyama@kurihama1.hosp.go.jp
Provenance:
Not commissioned; externally peerreviewed
Summary Points
!,$(ÈDEFICIENCYÈRESULTINGÈFROMÈTHEÈ
 ALDH2
Lys487 allele contributes toboth the alcohol flushing responseand an elevated risk of squamouscell esophageal cancer from alcoholconsumption.
+NOWLEDGEÈOFÈTHEÈFLUSHINGÈRESPONSEÈISÈ
useful clinically, as it allows doctors toidentify their ALDH2-deficient patientsin a simple, cost-effective, and non-invasive manner.
$OCTORSÈSHOULDÈCOUNSELÈTHEIRÈ!,$(
deficient patients to limit alcoholconsumption and thereby reduce therisk of developing esophageal cancer.
)NÈVIEWÈOFÈTHEÈAPPROXIMATELYÈÈ
million ALDH2-deficient individuals inthe world, many of whom now live inWestern societies, even a small percentreduction in esophageal cancers dueto a reduction in alcohol drinkingwould translate into a substantialnumber of lives saved.
Research in Translation discusses health interventionsin the context of translation from basic to clinicalresearch, or from clinical evidence to practice.
 
PLoS Medicine | www.plosmedicine.org0259March 2009 | Volume 6 | Issue 3 | e1000050
 ALDH2 activity. Because the Lys alleleacts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes havefar less than half of the ALDH2 activity of Glu/Glu homozygotes; in fact,the reduction in ALDH2 activity inheterozygotes is more than 100-fold [8]. Alcohol consumed by ALDH2-deficient individuals is metabolized toacetaldehyde, which accumulates inthe body due to absent ALDH2 activity and results in facial flushing (Figure1), nausea, and tachycardia [2]. Theseunpleasant effects are the result of diverse actions of acetaldehyde in thebody, including histamine release[10]. Because of the intensity of thisunpleasant response, ALDH2 Lys/Lyshomozygotes are unable to consumesignificant amounts of alcohol. As aresult, they are
 protected 
against theincreased risk of esophageal cancerfrom alcohol consumption [11]. Thisobservation also provided evidence for acausative role for ethanol in esophagealcancer, and a key role for acetaldehydein mediating this effect [11]. ALDH2 Lys/Glu heterozygotesexperience a less severe manifestationof the flushing response due to residualbut low ALDH2 enzyme activity intheir cells. As a result, some are ableto develop tolerance to acetaldehydeand the flushing response and becomehabitual heavy drinkers, due in part tothe influence of societal and culturalfactors (see below). Therefore,paradoxically, it is the more commonlow-activity ALDH2 heterozygousgenotype that is associated withgreatest risk of esophageal cancer fromdrinking alcohol.
Evidence That ALDH2 DeficiencyIncreases the Risk of Alcohol-Related Squamous Cell EsophagealCancer
Following the first study [12], which was conducted in the Japanesepopulation, case control studies in Japan and Taiwan have consistently demonstrated a strong link betweenthe risk of esophageal squamous cellcarcinoma (Figure 3) and alcoholconsumption in low-activity ALDH2heterozygotes, with odds ratios(ORs) ranging from 3.7 to 18.1 afteradjustment for alcohol consumption.Moreover, most studies show ORsof over 10 for increased risk inheterozygotes who are heavy drinkers[13,14]. An independent meta-analysishas also confirmed an increasedrisk, even among moderate drinkingheterozygotes [11]. In the Japaneseand Taiwanese studies, a strikingly high proportion (58%–69%) of theexcessive risk for esophageal cancer isattributable todrinking by low-activity  ALDH2 heterozygous individuals[13,14].Consistent with the results of casecontrol studies, prospective studiesin cancer-free alcoholics have alsoshown that the relative hazard forfuture upper aerodigestive tract (UADT) cancers in low-activity ALDH2heterozygotes is approximately 12 timeshigher than in individuals with active ALDH2 [15]. (The UADT includesthe oral cavity, pharynx, larynx, andesophagus.) In addition, alcoholconsumption in low-activity ALDH2heterozygotes has been associated with other cancer-related outcomes,including the presence of multipleareas of esophageal dysplasia (i.e.,premalignant lesions) and multipleindependent UADT cancers [13].It is important to note that ALDH2deficiency does not influenceesophageal cancer risk in non-drinkers[11]. Furthermore, the magnitudeof the ALDH2-associated esophagealcancer risk depends on the relativeimportance of alcohol versus other riskfactors in a given population. In ruralareas of China, where there is a highrate of esophageal cancer but alcoholdrinking plays a less important rolethan in Japan and Taiwan, there is amore modest positive association (ORs,1.7 to 3.1) between low-activity ALDH2heterozygotes and esophageal cancerrisk (e.g., [16]).
Acetaldehyde Is Responsible forFacial Flushing and EsophagealCancer Risk in ALDH2-DeficientIndividuals
 Acetaldehyde is responsible for thefacial flushing and other unpleasant effects that ALDH2-deficient 
doi:10.1371/journal.pmed.1000050.g001
Figure 1.
 The Alcohol Flushing Response
Facial flushing in a 22-year-old ALDH2 heterozygote before (left) and after (right) drinking alcohol. The individual pictured in this figure has given written consent for publication of his picture usingthe PLoS consent form.
doi:10.1371/journal.pmed.1000050.g002
Figure 2.
 The Ethanol Metabolic Pathway and the Role of the ALDH2 Variants inAcetaldehyde Accumulation
It should be noted that ADH is also polymorphic, and genetic variants in ADH1B interact with theALDH2 variant to modify risk [13].
 
PLoS Medicine | www.plosmedicine.org0260March 2009 | Volume 6 | Issue 3 | e1000050
individuals experience when they drink alcohol [10]. Importantly, thereis now direct evidence that ALDH2-deficient individuals experiencehigher levels of acetaldehyde-relatedDNA and chromosomal damage thanindividuals with fully active ALDH2 when they consume equivalent amounts of alcohol, providing a likely mechanism for the increased cancerrisk. A study in Japanese alcoholics [17]showed that the amount of mutagenicacetaldehyde-derived DNA adducts(Figure 4) in white blood cells wassignificantly higher in ALDH2-deficient heterozygotes than in individuals withactive ALDH2 (Table 1). In this study, while the two groups were matchedfor alcohol consumption, the ALDH2-deficient group consumed slightly lessalcohol on average than the controls. Also, ALDH2 heterozygotes who drankalcohol had higher levels of whiteblood cells with chromosomal damagethan drinkers with active ALDH2 [18].Because of these as well as other data,the 2007 International Agency forResearch on Cancer Working Groupon alcohol and cancer specifically noted the substantial mechanisticevidence supporting a causal rolefor acetaldehyde in alcohol-relatedesophageal cancer [19]. While the UADT is exposed toacetaldehyde from alcoholic beverages[20] and tobacco smoke, increasingevidence points to the metabolismof ethanol by microorganisms inthe oral cavity as an important source of acetaldehyde in salivaand, by extension, in the esophagus. Acetaldehyde levels in saliva are 10–20times higher than in blood, due to thelocal formation of acetaldehyde by oralmicroorganisms [21]. Importantly, ALDH2 heterozygotes had two to threetimes the acetaldehyde levels in theirsaliva compared to fully active ALDH2individuals after a moderate dose of oral ethanol [22].
Social and Cultural FactorsModulate Alcohol Drinking byALDH2 Heterozygotes
 Alcohol consumption is a socialactivity, and as such can be strongly influenced by cultural and social forces.In Japan, where the risk of alcohol-related esophageal cancer in ALDH2heterozygotes has been most welldocumented, going out drinking after work with colleagues is an essentialelement of Japanese business society,and the idea of group harmony isparticularly powerful. The percentageof heavy drinking men who are low-activity ALDH2 heterozygotes has risensubstantially in the last few decades,in parallel with the proliferation of business society in Japan and increasesin per capita alcohol consumption.Harada et al. [23] first reported that the frequency of inactive ALDH2 was very low (only 2%) in Japanesealcoholics in 1982. In a later study using archival DNA samples, Higuchi
doi:10.1371/journal.pmed.1000050.g003
Figure 3.
A Late-Stage Squamous CellCarcinoma of the Esophagus in a 51-Year-Old Male with a Known History of Flushingand Alcohol Drinking
doi:10.1371/journal.pmed.1000050.g004
Figure 4.
Chemical Structures of Deoxyguanosine, the DNA Base That Is the Target forAcetaldehyde, As Well As the Acetaldehyde-Derived DNA Lesions Referred To in Table 1
 The atoms in red represent the acetaldehyde-derived chemical modifications.
Five Key Papers in the Field
Harada et al., 1981
[2] The firstdocumentation of the relationshipbetween ALDH deficiency and theflushing reaction.
Yoshida et al., 1984
[9] Identification of the amino acid variant responsible forALDH deficiency.
Yokoyama et al., 1996
[12] The firstevidence demonstrating that ALDH2-deficient individuals have a dramaticallyelevated risk of esophageal cancer whenthey drink alcohol.
Yokoyama et al., 2003
[25]Demonstrates that an updated flushingquestionnaire containing two simplequestions is approximately 90% sensitiveand specific for identifying ALDH2-deficient individuals.
Baan et al., 2007
[19] Summary of theconclusions from the 2007 InternationalAgency for Research on Cancer WorkingGroup on the Consumption of AlcoholicBeverages. This is the first report toconclude thatethanol in alcoholicbeverages is carcinogenic to humans. The report also adds the female breastand colorectum to the list of sites foralcohol-related carcinogenesis and notessubstantial mechanistic evidence linkingacetaldehyde to esophageal cancer risk based on studies from ALDH2-deficientindividuals.

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