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Best Practice & Research Clinical Gastroenterology Vol. 17, No. 4, pp.

543 555, 2003


doi:10.1053/ybega.2003.377, www.elsevier.com/locate/jnlabr/ybega

4 Alcohol-related diseases of the mouth and throat


Frank Riedel* MD Ulrich Goessler MD Karl Hormann MD
Professor and Chairman Department of Otolaryngology, Head and Neck Surgery, University Hospital Mannheim, Theodor-Kutzer-Ufer, D-68135 Mannheim, Germany

Chronic consumption of alcoholic beverages is an accepted social custom worldwide. In the upper aerodigestive tract, local morphological, metabolic and functional alterations can be present as a result of alcohol consumption. A clinical link between the chronic consumption of alcohol and head and neck cancer has been observed for decades. While alcohol was described initially as a risk enhancer only in smokers, a number of epidemiological studies have now provided sufcient evidence that chronic alcohol consumption increases the risk of head and neck cancer independent of exposure to tobacco smoke. Systemic effects of alcohol interact with local changes in the morphology and function of the salivary glands. In addition, alcohol leads to the accumulation of pathological microbes within the mucosa, leading to chronic infection. Susceptibility to carcinogens and cell proliferation in the mucosa are increased, resulting in genetic changes with the development of dysplasia, leucoplakia and carcinoma. Chronic alcohol consumption has been correlated with an increased risk of cancer and increased mortality in a dose effect relationship. A number of biologically plausible mechanisms exist by which alcohol may cause cancer. These mechanisms are discussed in this chapter. Key words: alcohol; head and neck; squamous cell carcinoma; salivary glands; mucosa; microbes.

ALCOHOL AND THE RELATIVE RISK FOR HEAD AND NECK CANCER Heavy drinking and smoking are considered to be the most important risk factors for head and neck cancer.1 5 Evidence concerning a connection between smoking and head and neck cancer has been extensively documented. Many of the compounds in tobacco smoke are hazardous to health and some are undoubtedly carcinogenic. In contrast, the tumour-promoting effects of alcohol consumption are less well dened. Epidemiological data clearly indicate an independent carcinogenic
* Corresponding author. Tel.: 49-621-383-1600; Fax: 49-621-383-1972. E-mail address: frank.riedel@hno.ma.uni-heidelberg.de (F. Riedel). 1521-6918/03/$ - see front matter Q 2003 Published by Elsevier Science Ltd.

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effect of chronic alcohol consumption. Many excellent review papers have already dealt with this topic.6 11 Experimental studies have shown that pure ethanol is not itself mutagenic, clastogenic or carcinogenic.12 14 However, acetaldehyde, the primary metabolic product of ethanol has been shown to be mutagenic.15,16 In the multi-stage theory of head and neck carcinogenesis, alcohol is often regarded more as a co-carcinogenfacilitating tumour initiation or acting as a tumour promoter rather than as a tumour initiator itself.17,18 Thus, it has been concluded that contaminants and congenes are responsible for its association with cancer.19 Different groups have shown that head and neck cancer in people using alcohol and tobacco occurs approximately 15 years earlier than in non-smokers and nondrinkers.20 23 Feldman et al20 reported that non-smoking drinkers had a slightly increased risk for the development of head and neck cancer, but this result was without any statistical signicance. They suggested that the role of alcohol was of much less importance than that of tobacco or joint alcohol and tobacco exposure. In contrast, some other investigations have suggested that alcohol may have a greater inuence on head and neck cancer development.10,24 However, the synergistic effect of both seems to give higher risk ratios for head and neck cancer.25 Additionally, some authors have suggested that alcohol may have an independent effect.23,26 For example Tuyns10 suggested a denitely independent role for alcohol in oesophageal cancer, but he could not see this effect in head and neck cancer. In contrast to this result, most other studies and reviews, however, seem to conrm that alcohol does have an independent effect in increasing the risk of head and neck cancer.3,7,8,11,27 Herity et al28 found an increased risk for oral cancer of 4.6 for light drinkers and a ninefold increased risk for heavy drinkers. Llewelyn and Mitchell29 recently conrmed once again the association between alcohol and oral cancer, with a site predilection of tongue and oor of mouth. Jovanovic et al30 also found the oor of the mouth to be the high risk site for alcohol-related oral cancer.

THE DOSE EFFECT RELATIONSHIP In a clinical retrospective trial, Maier and Tisch31 detected a dose effect relationship between alcohol consumption and the incidence of head and neck carcinomas, with a maximum relative risk for hypopharyngeal carcinoma. Setting the relative risk (RR) for an individual with a daily alcohol consumption of 25 g at 1.0, there is an increase in the RR for cancer with higher amounts of alcohol, reaching a maximum of 32.4 at 100 g alcohol/day.31 After establishing the link between head and neck cancer and tobacco abuse, Tuyns et al5 found a RR of 12.5 for hypopharyngeal carcinoma with a consumption of 121 g alcohol/day, a RR of 10.6 for epilaryngeal carcinomas, RR 2.0 for supraglottic laryngeal carcinomas and RR 3.4 for glottic and subglottic carcinomas. Brugere et al25 found higher RR values with an alcohol consumption of 100 159 g/day: oral/tongue carcinomas, RR 13.1; oropharyngeal carcinomas, RR 15.2; hypopharyngeal carcinomas, RR 28.6. With a consumption above 160 g/day, the RR increases even more (oral cancer; RR 70; oropharyngeal cancer, RR 70; hypopharyngeal cancer, RR 143).25 Gronbaek et al32 established an increasing risk for head and neck cancer with increasing alcohol consumption, since they were able to show an 11.7-fold increase in the occurrence of head and neck cancer with the consumption of alcohol.

Alcohol-related diseases of the mouth and throat 545

ABSTENTION/ABUSE AND THE RELATIVE RISK FOR HEAD AND NECK CANCER Further evidence implicating alcohol as a pathogenetic factor for head and neck tumours has come from several studies of people that traditionally abstain from alcohol.33 Certain religious groups, such as the Seventh Day Adventists and Mormons, usually abstain from alcohol by church proscription and therefore provide researchers with opportunities to study the effect of alcohol drinking on cancer incidence and mortality.7 A lower than expected incidence of head and neck cancer has been reported for those religious groups compared with the general population.34 Wynder et al22 found that the frequency of cancer of the mouth, larynx and oesophagus among Seventh Day Adventists was only 13% of that seen among non-Adventists. Other studies have conrmed that there was a decreased risk of oral, pharyngeal and oesophageal cancers among Californian Seventh Day Adventists, based on mortality data. Cancer incidence and mortality among Mormons have also been studied. In Utah, where detailed cancer incidence rates are available, the incidence of cancer of the oral cavity, pharynx, oesophagus and larynx was 20 40% among Mormons compared with non-Mormons.35 In California, mortality rates among Mormon men were 53% for oral-pharyngeal, 45% for oesophageal and 30% for laryngeal cancer, respectively, compared with the general population of the USA.36 Even lower risks for these cancer sites were observed among active Mormons abstaining almost completely from the use of alcohol.36 Another option for investigating the effect of alcohol intake on cancer incidence and mortality is to look at alcoholics. Alcoholics, by denition, are addicted to the excessive use of alcohol. Their cancer mortality and incidence rates have been studied in several countries and compared with the prevailing rates in the general population.37 A three- to sixfold increased risk of head and neck cancer compared with the general population was reported for these alcoholics; the risk tended to be higher for oral and pharyngeal cancers than for laryngeal cancer. Cohort studies, looking at alcoholics in Norway, Sweden, Canada and the USA, have found an increased risk for oral cancer compared with the general population.7,25 Alcoholics were found to have signicantly more cancer cases than controls. The incidence for head and neck cancer was higher in the alcoholic group compared with the general population and alcoholics with head and neck cancer had been heavy drinkers and smokers for signicantly longer periods of time than alcoholics without head and neck abnormalities.38 Brewery workers are also presumed to drink a larger amount of beer than the general population. In cohort studies of brewery workers in Dublin, Denmark and Sweden, a relatively small, but statistically signicant, increase in the risk of head and neck cancer was found compared with the general population.39 41

TYPE OF ALCOHOLIC BEVERAGES Ethanol is present in alcoholic beverages as a consequence of the fermentation of carbohydrates with yeast. As well as ethanol, beer, wine and spirits also contain volatile and non-volatile avour compounds. Although the term volatile compound is rather diffuse, most of the compounds that occur in alcoholic beverages can be grouped according to whether they are distilled with alcohol and steam, or not.

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Volatile compounds include aliphatic carbonyl compounds, alcohols, monocarboxylic acids and their esters, nitrogen- and sulphur-containing compounds, hydrocarbons, terpenic compounds and heterocyclic and aromatic compounds. Non-volatile extracts of alcoholic beverages comprise unfermented sugars, di- and tribasic carboxylic acids, colouring substances, tannic and polyphonic substances and inorganic salts (for reviews, see Ogden & Wight8 and Wight & Ogden11). The type of alcoholic beverage has been regarded as being signicant and the results in the literature are often controversially discussed. The results of a case control study suggested that beer or wine drinkers had a much higher RR for the development of head and neck cancer than did whisky drinkers.3 Whisky drinkers consuming more than 10 whisky equivalent units per day had a RR of 7.3, whilst wine or beer drinkers had a RR of 20.4.3 In contrast to these results, beer and whisky have been implicated over wine42, while whisky has been implicated over beer and wine43 in other studies. Leclerc et al44 found that in cases of oral cancer a higher proportion of wine consumers was observed. Specic alcoholic beverages have been shown to contain specic impurities or contaminants that were found to be carcinogenic. For example, N-nitrosodiethylamine is present in some beers and whisky and has been associated with an increased risk of head and neck cancer.45 Carcinogenic polycyclic aromatic hydrocarbons have been found in many brands of whisky.46 Summarizing all the results, it seems that the total amount of alcohol7 and the duration of alcohol consumption38 are regarded as more important factors than the type or constitution of the alcoholic beverage consumed.

METABOLISM OF ETHANOL Alcohol dehydrogenase (ADH), microsomal ethanol oxidizing system (MEOS) and catalase are the most important enzymes that are involved in the metabolism of ethanol.8,11 Most alcohol is metabolized by alcohol dehydrogenase to acetaldehyde. It has been proposed that the major part of the carcinogenic potency of alcohol is mediated via this compound.47 There is increasing evidence for acetaldehyde to be the ultimate carcinogenic substance behind alcohol consumption. Acetaldehyde has been shown to be highly toxic, mutagenic and carcinogenic in different cell cultures and animal models.48 50 In experimental animal studies, histopathological changes after acetaldehyde treatment have been shown to mimic those known to occur after treatment with alcohol.51 Stronger evidence for acetaldehyde as the major factor behind ethanol-associated carcinogenesis is derived from studies linking the genotypes of ethanol-metabolizing enzymes with tumour risk. Rapidly metabolizing ADHs (ADH3), leading to a greater, faster production of cellular acetaldehyde, and the lack of the low Km aldehyde dehydrogenase, ALDH2, leading to a longer and delayed exposure to acetaldehyde, have recently been shown to be associated with increased cancer risk in the upper gastrointestinal tract.52 56 Various ALDH isoenzymes exist throughout the body, e.g. in the gastrointestinal tract, kidney, lungs, etc., each of which can show genetic variations.57 ADH and ALDH activity have been demonstrated in the oral cavity.58 Interestingly, the activity of the ALDH is much less than that of the ADH.59 This would suggest that it is possible for the cytotoxic acetaldehyde to accumulate in the oral tissues and may thus be a factor in alcohol-related oral disease.

Alcohol-related diseases of the mouth and throat 547

EFFECT OF ALCOHOL ON THE ORAL MUCOSA Experimental work has been carried out to look at morphological changes in the oral mucosa. Mascres et al60 looked at the effect on rat oesophageal mucosa of chronic ethanol exposure. They observed an epithelial atrophy following chronic alcohol consumption. The atrophy was due to a decrease in basal cellular size. Muller et al61 compared the effects of acute and chronic alcohol exposure on the oral mucosa in a rabbit animal model. Over the short-term, they observed varying degrees of tissue damage depending on the concentrations of alcohol used. In the long-term, they observed dysplastic changes with keratosis, increased density of the basal cell layer and a slightly increased number of mitotic gures. Maier et al62 also looked at the effects of chronic ethanol consumption on the oral mucosa in a rat animal model. They observed a signicant increase in the size of the basal cell layer and of basal cell nuclei from oral epithelium and an increase in the percentage of cells in the S-phase of the cell cycle. The mean epithelial thickness was reduced. They suggested that the chronic ethanol consumption had caused the oral mucosal atrophy with associated hyper-regeneration, which in turn may result in an enhanced susceptibility of the mucosal epithelium towards chemical carcinogens (see Figure 1). The underlying mechanisms of the increased proliferative activity of the mucosal epithelium of the oral cavity are still unclear, but it is believed that this hyper-regeneration might be caused by a cytotoxic effect of ethanol. Furthermore, in previous animal experiments62 and in human postmortem studies63 it has been shown that chronic ethanol consumption, as well as hyper-regeneration, causes atrophy of the oral and pharyngeal mucosa. Atrophy does not only occur in tissues that are in direct contact with ethanol such as the oral and the pharyngeal mucosa. Thus, it appears likely that ethanol not only exerts a local toxic

ALCOHOL

ORAL MICROBES

MUCOSA

SALIVA

Accumulation of pathogenic bacteria

Cell damage

Atrophy of glandular acini

Inflammation

Cell regeneration

Secretion Viscosity

Genetic Changes

Contact time of carcinogens

Figure 1. Effect of alcohol on oral microbes, oral mucosa and salivary glands.

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effect on the epithelium of the upper aerodigestive tract, but also interferes systemically with the metabolism of mucosal cells. Another pathway by which alcohol may affect the oral mucosa is through a direct effect of ethanol on the phospholipid bilayer of the cell membrane. The idea is that if the oral mucosa is exposed to a solvent such as alcohol that removes some of the lipid content, the mucosa becomes considerably more permeable. This might lead to an increased penetration of carcinogens across the oral mucosa.8,11,64 Ethanol has also been shown to enhance the penetration of the tobacco carcinogen nitrosonornicotine across the oral mucosa.65 In addition, Howie et al66 also demonstrated an increase in the permeability of human tongue in vitro to high molecular weight molecules in the presence of alcohol.

EFFECT OF ALCOHOL ON ORAL MICROBES As described above, smoking and chronic alcohol consumption can affect and decrease saliva ow.6,8,11 In the presence of a low saliva ow it is known that bacterial concentrations increase, and this might be an explanation for the higher total counts in these subjects.47 However, qualitative changes in the microbial ora in high acetaldehyde producers are also detectable, as already described for smokers.47 For instance, high acetaldehyde producers were shown to have an increased incidence of Candida albicans.47 In general, a microbial switch with a signicant increase in the proportion of Gram-positive versus Gram-negative bacteria has been described in smokers.67 70 This is in line with the results of Homann et al47 who showed that almost all aerobic Gram-positive bacteria were signicantly increased in high acetaldehyde producers, with the facultative commensals Staphylococcus sp. and S. mutans being the only exceptions. Gram-negative aerobic bacteria such as Haemophilus sp. and Neisseria sp. were not associated with higher acetaldehyde production. Microbial changes in the oral microora of alcoholics (see Figure 1) have been less intensively described.71 Epidemiological studies have shown that heavy drinking is associated with poor oral hygiene. It has been suggested that this may lead to bacterial overgrowth, but so far no study has convincingly proved this hypothesis and no bacterial species have been associated with high alcohol consumption.47,71 Since high salivary acetaldehyde production was observed only among heavy drinkers, enzyme induction might be an explanation for this nding. Bacteria are known to be easily able to induce the corresponding metabolizing enzymes.47 As mentioned above, there is epidemiological evidence indicating that alcohol has tumour-promoting effects.1 8,10,11,72,73 The pathogenetic mechanism of alcohol intake behind the epidemiological ndings could be the local production of carcinogenic acetaldehyde from ethanol by oral microbes. In a very recent study among Orientals, a possible correlation between ALDH2 genotype mutation and cancer risk in alcoholics has been expanded to all possible alcohol-related cancers. In this study, the frequency of a mutant ALDH2-2 allele was signicantly higher in alcoholics with oropharyngeal, laryngeal, oesophageal, stomach, colon and lung cancer, but not liver or other cancers.54 This is very interesting, since these organs are covered with microbes and microbial production of acetaldehyde from ethanol has been described.74 77 Thus, it is possible that the hampered detoxication of acetaldehyde from ethanol in ALDH2decient subjects might only become clinically relevant in cases of marked acetaldehyde production by microbes. Hence, there is conclusive experimental support for microbial

Alcohol-related diseases of the mouth and throat 549

acetaldehyde production from ethanol as a major factor in alcohol-associated carcinogenesis.47

EFFECT OF ALCOHOL ON SALIVA AND THE SALIVARY GLANDS Clinical enlargement of the parotid gland is often present in chronic alcoholics.78,79 Investigating the effect of chronic ethanol consumption on salivary gland morphology and function in a rat animal model, Maier et al80 found fat accumulation in acinar cells along with a reduction in weight and protein content of the parotid gland. They also demonstrated a reduction of salivary ow rates based on experiments with their animal model. This reduction of salivary ow might be due salivary gland atrophy.80 Simanowski et al64 suggested that a decrease in salivary ow would lead to a decreased clearing of mucosal surfaces (see Figure 1). This could lead to an accumulation and, consequently, to an increased exposure of the oral mucosa to carcinogens.81 Other investigations based on in vitro analysis demonstrated a reduction of mutagenic activity of some carcinogens by human saliva.82,83 Recently, local acetaldehyde production in the saliva by microbes has been described.84 The same group recently investigated the factors that regulate microbial production of acetaldehyde in saliva. Moreover, possible differences in microbial composition and relative concentrations among high and low acetaldehyde producers were examined.47 The group demonstrated that smoking and heavy alcohol consumption signicantly increase salivary acetaldehyde production. While smoking showed a positive linear correlation, alcohol seems to interact and increase salivary acetaldehyde production only if consumption is heavy (. 40 g/day); but when an increase is observed it is dose-dependent. Smoking and alcohol together increase salivary acetaldehyde production by , 100% compared with non-smokers and moderate alcohol consumers. It was concluded that these ndings could be a biologically plausible mechanism for explaining the synergistic and multiplicative manner by which the attributable cancer risks of alcohol and smoking act.47 Microbial salivary acetaldehyde production shows high interindividual variation, but there exists a signicant positive correlation between salivary ethanol and acetaldehyde levels. Moreover, in vivo salivary acetaldehyde levels correlate very signicantly with the levels that are produced in vitro. This offers the opportunity to use the in vitro salivary test as a tool to investigate possible variables that might inuence salivary acetaldehyde production. Salivary acetaldehyde levels after ethanol intake strikingly exceed those known to be derived from endogenous metabolism of ethanol.84 Salivary acetaldehyde may reach, via normal distribution and evaporation, all target tissues of the upper aerodigestive tract. Consequently, it is suggested that the major part of the carcinogenic role of alcohol is caused by its rst metabolite, acetaldehyde, which is microbially produced.47

EFFECT OF ALCOHOL ON THE DNA REPAIR MECHANISM Several authors have suggested that alcohol may have an effect on the DNA repair mechanisms.8,11,85,86 Some experiments have demonstrated that chronic ethanol consumption interferes with the repair of alkylated DNA.87,88 An increased risk for the development of head and neck cancer associated with combined increased chromosome sensitivity and increased alcohol consumption has been demonstrated.

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This has led to the suggestion that DNA repair capacity was inhibited, increasing susceptibility to environmental carcinogens such as alcohol.8,11 Hsu and Furlong17 looked at the effects of pulsed bleomycin with the addition of different concentrations of alcohol in vitro. After a bleomycin pulse with incubation in 0.5% alcohol, the frequencies of chromatid breaks steadily dropped as incubation time increased, but if 2% alcohol was used, the number of chromosome breakages remained high, suggesting that DNA repair was inhibited. This inhibition phenomenon was reversed when ethanol was removed from the growth medium.8,11,17

EFFECT OF ALCOHOL ON GENOTOXICITY Alcohol has been shown to potentiate the genotoxicity of mutagenic/clastogenic/carcinogenic agents.8,11 Hamster cheek pouches painted with the carcinogen dimethylbenzanthracene (DMBA) and alcohol developed larger epithelial tumours earlier than those painted with DMBA alone.89 Lin et al90 demonstrated, in vitro, that the clastogenicity of ultraviolet light and cytotoxic drugs was potentiated by treatment with alcohol. Hsu et al91 also looked at different mutagenic agents in vitro. They found that concurrent addition of alcohol increased the clastogenicity of all agents tested. In another in vitro experiment, Patel et al92 demonstrated that the clastogenicity of the genotoxic agent pan masala was potentiated by alcohol.

ALCOHOL AND ITS SYSTEMIC EFFECTS Deleyiannis et al93 investigated the prognosis of patients with head and neck cancer depending on alcohol consumption. He was able to show that patients who were alcoholics have a poorer prognosis than non-alcoholic patients. He suggested that this was, in part, due to an increased risk for other alcohol related diseases. Alcoholism and a history of alcohol related disorders were found to be associated with an increased risk of death, whereas abstinence (for at least one year prior to cancer diagnosis) was associated with a decreased risk of death.8,11,93 One reason for this might be the effect of chronic alcohol consumption on the livers ability to deal with toxic or potentially carcinogenic compounds.8,11,24,94,95 In addition to metabolic systemic effects, immunosuppressive effects of alcohol8,11,84, including T cell depression and decreased cytotoxicity of natural killer cells, might contribute to the worse prognosis of alcoholics compared to non-alcoholics. As well as this, alcohol consumption resulted in an increased number of chromosomal aberrations and sister chromatid exchange frequency in lymphocytes in a rat animal model.96 These data support the hypothesis that the co-carcinogenic activity of ethanol may not be limited to local effects, but through systemic effects it may be associated with chronic alcohol consumption. For example, it is known that alcoholics are not infrequently malnourished.97 Valin et al98 showed in vitro endogenous nitrosation of alcohol-related metabolites to produce mutagenic substances. The carcinogenicity of N-nitropyrrolidine, a tobacco-related carcinogen, has been shown to be enhanced in vivo in an animal model by chronic ethanol administration.24 Investigating various alcoholic beverages, Yamada et al99 found DNA methylation to be increased in the oesophagus after alcohol administration. They concluded that the beverages tested in this study may contain congeners that may themselves, or in synergy, cause a shift in nitrosamine metabolism from the liver to

Alcohol-related diseases of the mouth and throat 551

extra-hepatic tissues. Comparing the effect of ethanol on the metabolism of nitrosamine in different organs, Swann et al100 demonstrated a reduction in nitrosamines during rst pass clearance in the liver, which led to an increased metabolism in extrahepatic tissues. Their results suggested that the role of ethanol in carcinogenesis may be through its different effect on nitrosamines from tobacco smoke, diet and endogenous sources.100

ACKNOWLEDGEMENTS This work was supported by grants from the Research Fund of the Faculty of Medicine Mannheim, University of Heidelberg and of the Landesforschungsschwerpunkt Alkohol und Alkoholfolgekrankheiten of the State of Baden-Wurttemberg, Germany. Practice points epidemiological data clearly indicate an independent carcinogenic effect of alcohol intake a dose effect relationship between alcohol consumption and the incidence of head and neck carcinomas has been found a lower than expected incidence of head and neck cancer has been reported for groups that abstain from alcohol compared with the general population an increased risk of head and neck cancer compared with the general population was reported for alcoholics the total amount of alcohol and the duration of alcohol consumption seem to be more important factors than the type or constitution of the alcoholic beverage consumed clinical enlargement of the parotid gland is often present in chronic alcoholics

Research agenda there is increasing evidence for acetaldehyde to be the ultimate carcinogenic substance behind chronic alcohol consumption and this needs to be conrmed chronic alcohol consumption may affect the oral mucosa by a direct effect of ethanol on the phospholipid bilayer of the cell membrane leading to an increased penetration of carcinogens across the oral mucosa. Studies are needed to investigate this the pathogenetic mechanism of chronic alcohol consumption might be the local production of carcinogenic acetaldehyde from ethanol by oral microbes and this needs further study chronic alcohol consumption seems to interfere with the repair of alkylated DNA. This should be investigated further further studies are needed to see if alcohol might potentiate the genotoxicity of mutagenic/clastogenic/carcinogenic agents chronic alcohol consumption might inuence the livers ability to deal with toxic or potentially carcinogenic compounds. Further work is needed on this topic

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