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Hepatocellular carcinoma, alcohol, and cirrhosis: Facts and hypotheses

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Abstract

Despite the epidemiological evidence of a correlation between ethanol abuse and hepatocellular carcinoma, some of the results of experimental and clinical studies remain controversial. Apart from inducing cirrhosis, which may be viewed as a precancerous liver lesion, ethanol may act as a cocarcinogen. Most investigations on this topic have focused on two aspects: ethanol's capacity to induce the cytochrome P-450-dependent microsomal biotransformation system and its interference with at least one DNA repair mechanism. Ethanol exposure enhances the capacity of mixed function oxidases to activate many chemical carcinogens, such as dimethylnitrosamine (DMN). On the other hand, ethanol exposure fails to influence DMN-induced liver carcinogenesis. The capacity of alcohol to inhibit DMN-demethylase activity has not been clearly demonstrated in experiments carried out with human tissue. In conclusion, both the effects of ethanol and their underlying mechanisms as regards liver carcinogenesis are open to debate. The link between ethanol abuse and hepatocellular carcinoma appears to be mediated mainly by its capacity to induce cirrhosis.

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References

  1. Tuyns AJ, Pequignot G, Jensen OM: Le cancer de l'oesophage en Ille-et-Vilaine en fonction des niveaux de consommation d'alcool et de tabac. Des risques qui se multiplient. Bull Cancer 64:45–60, 1977

    Google Scholar 

  2. McMichael AJ: Increases in laryngeal cancer in Britain and Australia in relation to alcohol and tobacco consumption trends. Lancet 1:1244–1247, 1978

    Google Scholar 

  3. Keller AZ: Liver cirrhosis, tobacco, alcohol and cancer among blacks. J Natl Med Assoc 70:575–580, 1978

    Google Scholar 

  4. Austin H, Delzell E, Grufferman S, Levine R, Morrison AS, Stolley PD, Cole P: A case-control study of hepato-cellular carcinoma and the hepatitis B virus, cigarette smoking and alcohol consumption. Cancer Res 46:962–966, 1986

    Google Scholar 

  5. Stemhagen A, Slade J, Altman R, Bill J: Occupational risk factors and liver cancer in New Jersey. A retrospective case-control study of primary liver cancer. Am J Epidemiol 117:443–454, 1983

    Google Scholar 

  6. Nanji AA, French SW: Hepatocellular carcinoma. Relationship to wine and pork consumption. Cancer 56:2711–2712, 1985

    Google Scholar 

  7. Trichopoulos D, Dat NE, Kaklamani E, Tzonou A, Munoz N, Zavitzanos X, Kuomantaki Y, Trichopoulou A: Hepatitis B virus, tobacco smoking and ethanol consumption in the etiology of hepatocellular carcinoma. Int J Cancer 39:45–49, 1987

    Google Scholar 

  8. Shibata A, Hirohata T, Toshima H, Tashiro H: The role of drinking and cigarette smoking in the excess deaths from liver cancer. Gann 77:287–295, 1986

    Google Scholar 

  9. Norredam K: Primary carcinoma of the liver. Acta Pathol Microbiol Scand 87:227–236, 1979

    Google Scholar 

  10. Jensen OM: Cancer morbidity and causes of death among Danish brewery workers. Int J Cancer 23:454–463, 1979

    Google Scholar 

  11. Hakulinen T, Lehtimaki L, Lehtonen M, Teppo L: Cancer morbidity among two male cohorts with increased alcohol consumption in Finland. J Natl Cancer Inst 52:1711–1714, 1974

    Google Scholar 

  12. Qiao ZK, Halliday ML, Rankin JG, Coates RA: Relationship between hepatitis B surface antigen prevalence, per capita alcohol consumption and primary liver cancer death rate in 30 countries. J Clin Epidemiol 41(8):787–792, 1988

    Google Scholar 

  13. Lieber CS, Seitz HK, Garro AJ, Worner TM: Alcohol as a cocarcinogen.In Frontiers of Liver Disease. PD Berk, TC Chalmers (eds). Stuttgart, Thieme, 1981, pp 320–335

    Google Scholar 

  14. Gottfried EB, Steller R, Paronetto F, Lieber CS: Spontaneous regression of hepatocellular carcinoma. Gastroenterology 82:770–774, 1982

    Google Scholar 

  15. Peters RL: Pathology of hepatocellular carcinoma.In Hepatocellular Carcinoma. K Okuda, RL Peters (eds). New York, Wiley, 1976, pp 107–168.

    Google Scholar 

  16. Lee FI: Cirrhosis and hepatoma in alcoholic. Gut 7:77–85, 1966

    Google Scholar 

  17. Tuyns AJ, Pequignot G, Gignoux M, Valla A: Cancer of the digestive tract, alcohol and tobacco. Int J Cancer 30:9–11, 1982

    Google Scholar 

  18. Bartock I, Rememar E, Toth J: Clinicopathological studies of liver cirrhosis and hepatocellular carcinoma in a general hospital. Hum Pathol 12:794–803, 1981

    Google Scholar 

  19. Chan CH: Primary carcinoma of the liver. Med Clin North Am 59:989–994, 1975

    Google Scholar 

  20. Shikata T: Primary liver carcinoma and liver cirrhosis.In Hepatocellular Carcinoma. K Okuda, RL Peters (eds). New York, Wiley, 1976, pp 53–72

    Google Scholar 

  21. Farinati F, Chiaramonte M, Rugge M, Salvagnini M, Zagolin M, Guido M, Naccarato R: Hepatocellular carcinoma: Search for strategies in early diagnosis.In Pathophysiology of the Liver. P Gentilini, MU Dianzani (eds). New York, Elsevier, 1988, pp 217–226

    Google Scholar 

  22. Brechot C, Nalpas B, Courouce AM, Duhamel G, Gallard P, Carnot F, Tiollais P, Bertheloth P: Evidence that hepatitis B virus has a role in liver cell carcinoma in alcoholic liver disease. N Engl J Med 36:1384–1387, 1982

    Google Scholar 

  23. Blumberg BS, London WT: Hepatitis B virus and the prevention of primary cancer of the liver. J Natl Cancer Inst 74:267–273, 1985

    Google Scholar 

  24. Okuda K: Primary liver cancer. Quadriennal review lecture. Dig Dis Sci 9:133–146, 1986

    Google Scholar 

  25. Hino O, Kitagawa T, Sugano H: Relationship between serum and histochemical markers for hepatitis B virus and rate of viral integration in hepatocellular carcinoma in Japan. Int J Cancer 35:5–10, 1985

    Google Scholar 

  26. Imazeki F, Omata M, Yokosuka O, Okuda K: Integration of hepatitis B virus DNA in hepatocellular carcinoma. Cancer 58:1055–1060, 1986

    Google Scholar 

  27. Goudeau A, Maupas P, Dubois F, Coursaget P, Bougnoux P: Hepatitis B infection in alcoholic liver disease and primary hepatocellular carcinoma in France. Progr Med Virol 27:26–34, 1981

    Google Scholar 

  28. Gluud C, Aldershville T, Henriksen J, Kryger P, Mathieson L: Hepatitis B and A virus antibodies in alcoholic steatosis and cirrhosis. J Clin Pathol 35:693–697, 1982

    Google Scholar 

  29. Ohnishi K, Iida S, Iwana S, Gato N, Nomura F, Takashi M, Mishima A, Kono K, Kimura K, Musha H, Kotota K, Okuda K: The effect of chronic habitual alcohol intake on the development of liver cirrhosis and hepatocellular carcinoma. Cancer 49:672–677, 1982

    Google Scholar 

  30. Walter E, Blum HE, Meier P, Huonker M, Schmid M, Maier KP, Offensperger WB, Offensperger S, Gerok W: Hepatocellular carcinoma in alcoholic liver disease: no evidence for a pathogenetic role of hepatitis B virus infection. Hepatology 8(4):745–748, 1988

    Google Scholar 

  31. Chiaramonte M, Farinati F, Fagiuoli S, Ongaro G, Anneloni V, Vicarioto M, Naccarato R: Antibody to hepatitis C virus in hepatocellular carcinoma. Lancet 1:301–302, 1990

    Google Scholar 

  32. Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanches JM, Ventura M, Vall M, Bruguera M, Bru C, Castillo R, Rodes J: Prevalence of antibodies to hepatitis C Virus in Spanish patients with hepatocellular carcinoma and cirrhosis. Lancet 2:1004–1006, 1989

    Google Scholar 

  33. Ketcham AS, Wexler H, Mantel N: Effects of alcohol in mouse neoplasia. Cancer Res 23:667–670, 1963

    Google Scholar 

  34. Schottenfeld D: Alcohol as a co-factor in the etiology of cancer. Cancer 43:1962–1966, 1979

    Google Scholar 

  35. McCoy GD, Hecht SS, Katayama S, Wynder EL: Differential effects of chronic ethanol consumption on the carcinogenicity of N-nitrosopyrrolidine and N-nitrosonornicotina in male Syrian golden hamsters. Cancer Res 41:2849–2854, 1981

    Google Scholar 

  36. Radike MJ, Stemmer KL, Bingham E: Effect of ethanol on vinychloride carcinogenesis. Environ Health Perspect 4:59–63, 1981

    Google Scholar 

  37. Lieber CS, De Carli LM: The feeding of ethanol: A decade of application and a 1982 update. Clin Exp Res 6:523–531, 1982

    Google Scholar 

  38. Kuratsune M, Kohohi S, Horie A, Nishizumi M: Test of alcoholic beverages and ethanol solutions for carcinogenicity and tumor-promoting activity. Gann 62:395–405, 1965

    Google Scholar 

  39. Walker EA, Castegnaro M, Garren L, Touissaint G, Kowalski B: Intake of volatile nitrosamines from consumption of alcohols. J Natl Cancer Inst 63:947–951, 1979

    Google Scholar 

  40. Masuda Y, Mori K, Hirohata T, Karatzune M: Carcinogenesis in the esophagus. III Polycyclic aromatic hydrocarbons and phenois in whiskey. Gann 57:549–557, 1966

    Google Scholar 

  41. Cunningham HM, Pontetract R: Asbestos fibers in beverages and drinking water. Nature 232:332–333, 1971

    Google Scholar 

  42. Biles B, Emerson TR: Examination of fibers in beer. Nature 219:93–94, 1968

    Google Scholar 

  43. Lieber CS, Garro AJ, Leo MA, Mak KM, Worner T: Alcohol and cancer. Hepatology 6:1005–1019, 1986

    Google Scholar 

  44. Pottern LM, Morris LE, Blot WJ, Ziegler RG, Fraumeni JF: Esophageal cancer among black men in Washington, D.C.I. Alcohol, tobacco and other risk factors. J Natl Cancer Inst 67:777–783, 1981

    Google Scholar 

  45. Ziegler RG, Morris LE, Blot WJ, Pottern LM, Hoover R, Fraumeni JF: Esophageal cancer among black men in Washington D.C. II. Role of nutrition. J Natl Cancer Inst 67:1199–1206, 1981

    Google Scholar 

  46. Wynder EL, Hultberg S, Jacobson F, Bros IJ: Environmental factors in cancer of the upper alimentary tract: Swedish study with special reference to Plummer-Vinson (Paterson-Kely) syndrome. Cancer 10:470–487, 1957

    Google Scholar 

  47. Kmet J, Mahboudi E: Esophageal cancer in the Caspian littoral of Iran: initial studies. Sciences 175:846–853, 1972

    Google Scholar 

  48. Gabriel GN, Schrager TF, Newberne PM: Zinc deficiency, alcohol and retinoid: association with oesophageal cancer in rats. J Natl Cancer Inst 68:785–789, 1982

    Google Scholar 

  49. Vallee BC, Wacher WE, Bartholomay AF: Zinc metabolism in hepatic disfunction. I serum zinc concentrations in Laenneo's cirrhosis and their validation by sequential analysis. N Engl J Med 255:403–408, 1956

    Google Scholar 

  50. Sullivan JF, Lankford HG: Urinary excretion of zinc in alcoholism and post alcoholic cirrhosis. Am J Clin Nutr 10:153–157, 1962

    Google Scholar 

  51. Farinati F, Cardin F, Di Mario F, Costa F, Scapolo M, Venturi Pasini C, Bortolami M, De Lazzari F, Naccarato R: Genetic, dietary and environmental factors in the pathogenesis of gastric cancer. Study of a high incidence family. Ital J Gastroenterol 19:321–324, 1987

    Google Scholar 

  52. Leo MA, Lieber CS: Hepatic vitamin A depletion in alcoholic liver injury in man. N Engl J Med 307:597–601, 1982

    Google Scholar 

  53. Leo MA, Lieber CS: Interaction of ethanol with vitamin A. Alcoholism. Clin Exp Res 7:15–21, 1983

    Google Scholar 

  54. Smith FR, Goodman DS: The effect of disease of the liver, thyroid and kidneys on the transport of vitamin A in human plasma. J Clin Invest 50:2426–2436, 1971

    Google Scholar 

  55. Berenyi MR, Staus B, Cruz D:In vitro andin vivo studies of cellular immunity in alcoholic cirrhosis. Am J Dig Dis 19:199–205, 1974

    Google Scholar 

  56. Bernstein IM, Webster KE, Williams RC Jr, Strikland RG: Reduction in circulating T lymphocytes in alcoholic liver disease. Lancet 2:488–489, 1974

    Google Scholar 

  57. Seitz HK, Garro AJ, Lieber CS: Sex dependent effect of chronic ethanol consumption in rats on hepatic microsome mediated mutagenicity of benzo(a)pyrene. Cancer Lett 13:97–102, 1981

    Google Scholar 

  58. Seitz HK, Garro AJ, Lieber CS: Effect of chronic ethanol ingestion on intestinal metabolism and mutagenicity of benzo(a)pyrene. Biochem Biophys Res Commun 85:1061–1066, 1978

    Google Scholar 

  59. Seitz HK, Garro AJ, Lieber CS: Enhanced pulmonary and intestinal activation of procarcinogens and mutagens after chronic ethanol consumption in the rat. Eur J Clin Invest 11:33–38, 1981

    Google Scholar 

  60. Farinati F, Zhou ZC, Bellah J, Lieber CS, Garro AJ: Effect of chronic ethanol consumption on activation of nitrosopyrolidine to a mutagen by rta upper alimentary tract, lung and hepatic tissue. Drug Metab Dispos 13:210–214, 1985

    Google Scholar 

  61. Garro AJ, Seitz HK, Lieber CS: Enhancement of dimethylnitrosamine metabolism and activation to a mutagen following chronic ethanol conumption. Cancer Res 41:120–124, 1981

    Google Scholar 

  62. Schwartz M, Appel KE, Schrenk K, Kunz W: Effect of ethanol on microsomal metabolism of dimethylnitrosamine. J Cancer Res Clin Oncol 97:233–240, 1980

    Google Scholar 

  63. Griciute L, Castegnaro M, Bereziat JC: Influence of ethyl alcohol on carcinogenesis withN-nitrose-dimethylamine. Cancer Lett 13:345–352, 1981

    Google Scholar 

  64. Teschke R, Minzlaff M, Oldiges H, Frenzel H: Effect of chronic alcohol consumption on tumor incidence due to dimethylnitrosamine administration. J Cancer Res Clin Oncol 106:58–64, 1983

    Google Scholar 

  65. Tomera JF, Skipper PI, Wishnok JS, Tannenbaum SR, Brunengraber H: Inhibition ofN-nitrosamine metabolism by ethanol and other inhibitors in the isolated, perfused rat liver. Carcinogenesis 5:113–116, 1984

    Google Scholar 

  66. Swann PF, Coe AM, Mace R: Ethanol and dimethylnitrosamine and diethylnitrosamine metabolism and disposition in the rat. Possible relevance to the influence of ethanol on human cancer incidence. Carcinogenesis 5:1337–1343, 1984

    Google Scholar 

  67. Lieber CS, Garro AJ, Leo MA, Mak KM, Worner T: Alcohol and cancer. Hepatology 6:1005–1019, 1986

    Google Scholar 

  68. Zordan M, Farinati F, Nitti D, Levis AG, Naccarato R: Normal and pathological human liver dimethylnitrosamine demethylase activity and capacity for 2-aminofluorene and nitrosopyrrolidine activationin vitro. Hum Toxicol 8:164–165, 1989

    Google Scholar 

  69. Obidoa O, Okolo TC: Effect of ethanol administration on the metabolism of aflatoxin B1. Biochem Med 22:145–148, 1979

    Google Scholar 

  70. Mendenhall CL, Chedid LA: Peliosis hepatitis: its relationshp to chronic alcoholism, aflatoxin B1 and carcinogenesis in male Holtzman rats. Dig Dis Sci 25:587–592, 1980

    Google Scholar 

  71. Columbano A, Rajalakashmi S, Sarma DSR: Requirements of cell proliferation for the initiation of liver carcinogenesis as assayed by three different procedures. Cancer Res 41:2079–2083, 1981

    Google Scholar 

  72. Takada A, Jinichi N, Takase S, Matzuda Y: Effects of ethanol on experimental carcinogenesis. Hepatology 6:65–72, 1986

    Google Scholar 

  73. Guechot J, Peigney N, Ballet F, Vaubourdolle M, Giboudeau J, Poupon R: Sex hormone imbalance in male alcoholic cirrhotic patients with and without hepatocellular carcinoma. Cancer 62:760–762, 1988

    Google Scholar 

  74. Kohigashi K, Fukuda Y, Imura H: Estrogen receptors in hepatocellular carcinoma: is endocrine therapy for hepatocellular carcinoma likely to be effective. Gastroenterol Jpn 22:322–330, 1987

    Google Scholar 

  75. Van Thiel DH, Lester R: The effect of chronic alcohol abuse on sexual function. Clin Endocrinol Metab 8:499–451, 1979

    Google Scholar 

  76. Eagon PK, Porter LE, Francavilla A, Dileo A, Van Thiel DH: Estrogen and androgen receptors in liver: their role in liver disease and regeneration. Sem Liver Dis 5:59–69, 1985

    Google Scholar 

  77. Van Thiel DH, Gavaler JS: Ethanol and the endocrine system.In Alcohol-Related-Diseases in Gastroenterology, HK Seitz, et al (eds). Berlin, Springer-Verlag, 1985, pp 324–331

    Google Scholar 

  78. Garro AJ, Espina N, Farinati F, Salvagnini M: The effects of chronic ethanol consumption on carcinogen metabolism and on O6-methylguanine transferase activity-mediated repair of alkylated DNA. Alcohol Clin Exp Res 10:73s-77s, 1987

    Google Scholar 

  79. Farinati F, Espina N, Lieber CS, Garro AJ:In vivo inhibition by chronic ethanol exposure of O6-methylguanine transferase activity and DNA repair. Ital J Gastroenterol 17:48–49, 1985

    Google Scholar 

  80. Espina J, Lima V, Lieber CS, Garro AJ:In vitro andin vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase. Carcinogenesis 761–766, 1988

  81. Farinati F, Salvagnini M, Garro AJ, Naccarato R: Ethanol and carcinogenesis: promoter, co-carcinogen or innocent bystander? Ital J Gastroenterol 20:322–330, 1988

    Google Scholar 

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  1. Cattedra Malattie Apparato Digerente, Divisione di Gastroenterologia “R. Farini”, Istituto di Medicina Interna, Policlinico Universitario, Via Giustiniani 2, Padua, Italy

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Naccarato, R., Farinati, F. Hepatocellular carcinoma, alcohol, and cirrhosis: Facts and hypotheses. Digest Dis Sci 36, 1137–1142 (1991). https://doi.org/10.1007/BF01297461

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