132 REVIEW Cocarcinogenic effects of alcohol in Gut: first published as 10.1136/gut.51.1.132 on 1 July 2002. Downloaded from hepatocarcinogenesis F Stickel, D Schuppan, E G Hahn, H K Seitz ............................................................................................................................. Gut 2002;51:132–139 Alcohol is a major aetiological factor in INTRODUCTION hepatocarcinogenesis but our understanding of its Hepatocellular carcinoma (HCC) is the most frequent primary liver tumour among the com- importance as a modulating factor is just beginning to monest malignant tumours today.1 Its prevalence emerge. In the present review, a number of possible is increasing worldwide but differs greatly be- cofactors and mechanisms are discussed by which tween regions, with incidences of approximately 3–4/100 000 in Western countries2–4 and up to alcohol may enhance the development of hepatoma. 120/100 000 in Asia and Southern Africa. In more These include dietary or environmental carcinogens than 80% of European and North American cases, ingested along with alcoholic beverages, alcoholic HCCs develop in cirrhotic livers whereas in Asia near 50% of HCCs may occur in non-cirrhotic cirrhosis as a precancerous condition, and the effects of livers.56The increase in HCC is most likely due to alcohol metabolism. the more widespread chronic infection with .......................................................................... hepatotropic viruses, namely hepatitis B (HBV) and especially hepatitis C (HCV). Epidemiological studies have incriminated both viruses in hepato- SUMMARY carcinogenesis, and the contributory role of alco- The incidence of hepatocellular carcinoma is ris- hol, a major aetiological factor of liver cirrhosis in ing worldwide. Apart from hepatitis B and C Western countries, is undisputed.1 In the follow- viruses, alcohol presents a major aetiological fac- ing, we summarise the evidence and discuss tor in hepatocarcinogenesis, as shown in numer- potential mechanisms of the cocarcinogenic effect ous epidemiological studies. While the patho- of alcohol. genic role of alcohol in the development of liver http://gut.bmj.com/ cirrhosis has been investigated extensively, our EPIDEMIOLOGY understanding of its importance as a modulating There is compelling evidence that chronic alcohol factor in hepatocarcinogenesis is just beginning consumption increases the risk of developing to emerge. In the present review, a number of HCC.7–9 However, the exact role of alcohol in the possible cofactors and mechanisms are discussed development of HCC compared with chronic HBV by which alcohol may enhance the development and HCV infection is still incompletely defined. of hepatoma. These include dietary or environ- Numerous studies demonstrated that the inci- on September 23, 2021 by guest. Protected copyright. mental carcinogens ingested along with alcoholic dence of HCC among alcoholics is above the beverages, alcoholic cirrhosis as a precancerous expected rate.10 Thus an epidemiological survey condition, and the effects of alcohol metabolism from the UK demonstrated an eightfold increase such as the toxicity of its metabolite acetalde- in the risk of developing HCC among male hyde, increased lipid peroxidation due to reactive alcoholics.11 The higher rate of alcohol related oxygen species, activation of procarcinogens via HCC worldwide may be partially explained by induction of cytochrome P450 2E1, and polymor- prolongation of survival time of patients with phisms of alcohol dehydrogenase. Furthermore, alcoholic cirrhosis due to improved disease man- alterations of DNA methylation through interac- agement. tions with one carbon metabolism can lead to aberrant methylation of tumour suppressor genes and oncogenes. Alcohol metabolism also “Chronic alcohol consumption increases reduces hepatic retinoic acid levels and may the risk of developing HCC” thereby enhance cell proliferation and malignant See end of article for transformation via upregulation of activator pro- The effect of abstinence in the development of authors’ affiliations ....................... tein 1 gene expression. Synergistic effects be- HCC was discussed controversially in various tween alcohol and hepatitis B and especially C studies. It was shown that cessation of alcohol Correspondence to: virus have been demonstrated, although the Dr F Stickel, Department of mechanisms remain unclear. Alcohol leads to Medicine I, Division of ................................................. malfunction of the immune system, and suppres- Hepatology, University Abbreviations: AA, acetaldehyde; ADH, alcohol Erlangen-Nuremberg, sion of natural killer cells by alcohol may favour dehydrogenase; AFB , aflatoxin B ; ALD, alcoholic liver Krankenhausstraβe 12, 1 1 tumour development. Thus alcohol is commonly disease; ALDH, aldehyde dehydrogenase; DMN, D-91054 Erlangen, dimethyl-nitrosamine; CYP 2E1, cytochrome P450 2E1; Germany; felix. considered a tumour promoter. However, evi- [email protected] dence from animal studies that showed pre- HBV, hepatitis B virus; HCC, hepatocellular carcinoma; neoplastic alterations after chronic alcohol expo- HCV, hepatitis C virus; MB, Mallory body; NK, natural Accepted for publication sure indicate that alcohol may also contribute to killer; RA, retinoic acid; ROS, reactive oxygen species; 21 August 2001 SAH, S-adenosylhomocysteine; SAM, S-adenosyl- ....................... tumour initiation. methionine; TNF-α, tumour necrosis factor α. www.gutjnl.com Ethanol and HCC 133 consumption increased the risk of developing HCC. This was number of metabolic alterations—for example, enzyme explained by alterations in cell regeneration after alcohol altered foci and preneoplastic nodules.16 Recently, such areas withdrawal, which will be discussed below. However, a major of preneoplastic tissue were also produced in rats by alternate plausible argument is that abstinence allows recovery from treatment with N-nitrosodimethylamine as a cancer inducer Gut: first published as 10.1136/gut.51.1.132 on 1 July 2002. Downloaded from alcohol related hepatocellular damage which by prolonging and alcohol, strongly suggesting that ethanol may indeed act survival time may by itself increase the likelihood of develop- as a tumour promoter in hepatocarcinogenesis (fig 1).17 Inter- ing HCC in a cirrhotic liver. estingly, Mallory body (MB) formation is high in HCC and the incidence of HCC is significantly higher in cirrhosis with MBs 18 ANIMAL EXPERIMENTS than without. It was therefore hypothesised that MBs may Experiments in which alcohol but no carcinogen was given represent an initial phenotypical alteration in the carcinogenic continuously to rodents have shown that alcohol per se is not transformation of hepatocytes. a carcinogen as even lifelong exposure to alcohol did not lead Another histological abnormality observed in experimental to more cancers than in pair fed controls.8 Most animal hepatocarcinogenesis is the occurrence of oval cells which experiments with respect to hepatocarcinogenesis have been originate from the portal triads after long term alcohol 19 performed using nitrosamines as tumour inducing com- exposure. These cells do also appear after administration of a pounds. Unexpectedly, in almost all of these studies inhibition choline deficient ethionine supplemented diet which is known 20 of hepatocarcinogenesis together with alcohol intake was to stimulate hepatocarcinogenesis. Recently, the occurrence shown.8 On the other hand, the rate of extrahepatic tumours, of oval cells has also been observed in patients with chronic 21 such as tumours in the nasal cavity, trachea, and oesophagus, alcoholic liver disease. increased. Only with additional manipulations, such as Alcohol and environmental carcinogens administration of a diet low in methyl donors or Alcoholics may be exposed to carcinogens or procarcinogens carbohydrates,12 13 or after partial hepatectomy,14 was alcohol ingested along with alcoholic beverages which may contain able to stimulate hepatocarcinogenesis. Interestingly, striking nitrosamines, polycyclic hydrocarbons, asbestos fibres, and enhancement of hepatic carcinogenesis was observed when fusel oils.22 In addition, many alcoholics are smokers and epi- alcohol and the procarcinogen were given on an alternating demiological surveys have shown a hyperadditive effect of basis to avoid interactions between alcohol and carcinogen alcohol and smoking in increasing the risk of developing metabolism. Another important determinant in animal stud- HCC.9 Similarly, dietary carcinogens and exposure to carcino- ies of alcohol is the route of administration. If ethanol is given gens at the working place have to be taken into account (see with drinking water, nutrient deficiencies may occur due to fig 1). With regard to the former, aflatoxin B (AFB ) is a major interactions with their absorption that may influence carcino- 1 1 hepatocarcinogen which is metabolised by the alcohol induc- genesis. Administration of ethanol as a liquid diet, a technique ible cytochrome P450 2E1 (CYP 2E1). AFB can induce a established by Lieber and DeCarli,15 assures constant alcohol 1 mutation in codon 249 of the p53 tumour suppressor gene intake and provides adequate amounts of macro and which is frequently found in human HCC.23 micronutrients. “Many alcoholics are smokers and epidemiological http://gut.bmj.com/ PATHOMECHANISMS surveys have shown a hyperadditive effect of alcohol For the liver, there are multiple mechanisms by which alcohol and smoking in increasing