Hepatocellular carcinoma in alcoholic liver disease: mechanistic considerations and clinical facts

Abstract

Alcoholic hepatocellular carcinoma (AHCC) represents a lethal stage, emerging in the course of severe injurious stages of alcoholic liver disease including cirrhosis. AHCC only affects a few alcohol consumers, certainly not all individuals who consume large amounts of alcohol over a long period of time, suggesting a role of yet unknown genetic risk or protection factors. Most likely, hepatic DNA is ultimately involved, attacked by intermediate products derived from reactive oxygen species (ROS) generated from cytochrome P450 2E1 of the NADPH and oxygen dependent microsomal ethanol-oxidizing system whereby ethanol is metabolized. Ethanol and acetaldehyde are activated to procarcinogens, to be promoted to ultimate carcinogens by ROS and causatives for AHCC instead of any other putative chemical contained in alcoholic beverages. Prevention of HCC associated with cirrhosis is best accomplished by early recognition of alcohol abuse at the stage of alcoholic fatty liver rather than alcoholic hepatitis (AH) or alcoholic steatohepatitis (ASH), leading to the advice of consequent abstinence from alcohol. Abstinence early started effectively prevents AHCC development, as opposed to late begin of abstinence that lacks risk reduction. Although drug therapy may partially be effective in AH or ASH, no established drug options are available for a realistic therapy of AHCC. Liver transplantation is controversially discussed and can be considered, but may be an option for only a few patients on a case by case base. In conclusion, AHCC results from a ROS dependent conversion of ethanol and acetaldehyde to procarcinogens as promoters of AHCC.

Keywords

Alcohol / alcoholic liver disease / alcoholic cirrhosis / alcoholic hepatocellular carcinoma / microsomal ethanol-oxidizing system / cytochrome P450 2E1 / reactive oxygen species / carcinogens

References

[1] WHO. Cancer. Available from: https://www.who.int/news-room/fact-sheets/detail/cancer. [Last accessed on 6 Nov 2019]

[2] Crawford JM.Histologic findings in alcoholic liver disease..Clin Liver Dis2012;16:699-716

[3] Rawla P,Muralidharan P.Update in global trends and aetiology of hepatocellular carcinoma..Contemp Oncol (Pozn)2018;22:141-50 PMCID:PMC6238087

[4] Wu D, Cederbaum AI. Alcohol, oxidative stress, and free radical damage. Available from: https://pubs.niaaa.nih.gov/publications/arh27-4/277-284.htm. [Last accessed on 6 Nov 2019]

[5] Seitz HK,Cortez-Pinto H,Gual A.Alcoholic liver disease..Nat Rev Dis Prim2018;4:16

[6] Testino G,Borro P.Alcohol and hepatocellular carcinoma: a review and a point of view..World J Gastroenterol2014;20:15943-54 PMCID:PMC4239482

[7] Matsushita H.Alcohol and hepatocellular carcinoma..BMJ Open Gastro2019;6:e000260

[8] Teschke R.Alcoholic liver disease: current mechanistic aspects with focus on their clinical relevance..Biomedicines2019;7:68 PMCID:PMC6783919

[9] Logan BK.Endogenous ethanol “auto-brewery syndrome” as a drunk-driving defence challenge..Med Sci Law2000;40:206-15

[10] Cordell BJ,Miller GK.Case-control research study of auto-brewery syndrome..Global Adv Health Med2019;8:1-7 PMCID:PMC6475837

[11] Jolly NP,Pretorius IS.The role and use of the non-Saccharomyces yeasts in wine production..S Afr J Enol Vitic2006;27:15-39

[12] Moreno-Arribas MV.Wine Chemistry and Biochemistry.2009;Springer New York

[13] Seitz HK,Simanowski UA,Eckey R.Human gastric alcohol dehydrogenase activity: effect of age, gender and alcoholism..Gut1993;34:1433-7 PMCID:PMC1374557

[14] Cederbaum AI.Alcohol metabolism..Clin Liver Dis2012;16:667-85 PMCID:PMC3484320

[15] Teschke R.Alcoholic liver disease: alcohol metabolism, cascade of molecular mechanisms, cellular targets, and clinical aspects..Biomedicines2018;6:106 PMCID:PMC6316574

[16] Teschke R.Biochemical aspects of the hepatic microsomal ethanol-oxidizing system (MEOS): resolved initial controversies and updated molecular views..Biochem Pharmacol (Los Angel)2019;8:267

[17] Salaspuro M.Bircher J,McIntyre N,Rodes J.Epidemiological aspects of alcohol and alcoholic liver disease, ethanol metabolism, and pathogenesis of alcoholic liver injury..Oxford Textbook of Clinical Hepatology.1999;Oxford University Press, Oxford791-810

[18] Teschke R.Microsomal ethanol-oxidizing system (MEOS): success over 50 years and an encouraging future..Alcohol Clin Exp Res2019;43:386-400

[19] Lieber CS.Ethanol oxidation by hepatic microsomes: adaptive increase after ethanol feeding..Science1968;162:917-8

[20] Lieber CS.Hepatic microsomal ethanol-oxidizing system. In vitro characteristics and adaptive properties in vivo..J Biol Chem1970;245:2505-12

[21] Teschke R,Joly JG,Lieber CS.Microsomal ethanol-oxidizing system (MEOS): purification and properties of a rat liver system free of catalase and alcohol dehydrogenase..Biochem Biophys Res Commun1972;49:1187-93

[22] Teschke R,Lieber CS.Hepatic microsomal ethanol oxidizing system: solubilization, isolation and characterization..Arch Biochem Biophys1974;163:404-15

[23] Teschke R,Lieber CS.NADPH-dependent oxidation of methanol, ethanol, propanol, and butanol by hepatic microsomes..Biochem Biophys Res Commun1974;60:851-7

[24] Teschke R,Lieber CS.Hepatic microsomal alcohol-oxidizing system: affinity for methanol, ethanol, propanol and butanol..J Biol Chem1975;250:7397-404

[25] Teschke R, Zhu Y. Opinion: intestinal microbiome, endotoxins, cytochrome P450 2E1, and the gut-liver axis in alcoholic liver disease EC Gastroenterology Dig Syst. 2019;6.2:66-75. Available from: https://www.ecronicon.com/ecgds/pdf/ECGDS-06-00312.pdf [Last accessed on 6 Nov 2019]

[26] Hasumura Y,Lieber CS.Characteristics of acetaldehyde oxidation in rat liver mitochondria..J Biol Chem1976;251:4908-13

[27] Hasumura Y,Lieber CS.Acetaldehyde oxidation by hepatic mitochondria: its decrease after chronic ethanol consumption..Science1975;189:727-9

[28] Damgaard SE.The D(V/K) isotope effect of the cytochrome P-450-mediated oxidation of ethanol and its biological applications..Eur J Biochem1982;125:593-603

[29] Ohnishi K.Reconstitution of the microsomal ethanol-oxidizing system. Qualitative and quantitative changes of cytochrome P-450 after chronic ethanol consumption..J Biol Chem1977;252:7124-31

[30] Teschke R,Hasumura Y.Ullrich V,Hildebrandt A,Conney AH.Hepatic microsomal ethanol oxidizing system: isolation and reconstitution..Microsomes and Drug Oxidations.1977;Pergamon Press, Oxford103-10

[31] Miwa GT,Thomas PE.The direct oxidation of ethanol by a catalase-free and alcohol dehydrogenase-free reconstituted system containing cytochrome P-450..Arch Biochem Biophys1978;187:464-75

[32] Asai H,Kuroki T,Funnae Y.Microsomal ethanol oxidizing system activity by human hepatic cytochrome P-450s..J Pharmacol Exp Ther1996;277:1004-9

[33] Lieber CS.Cytochrome P-4502E1: its physiological and pathological role..Physiol Rev1997;77:517-44

[34] Cederbaum AI,Rubin E.The effect of dimethylsulfoxide and other radical scavengers on the oxidation of ethanol by rat liver microsomes..Biochem Biophys Res Commun1977;78:1254-62

[35] Ohnishi K.Respective role of superoxide and hydroxyl radical in the activity of the reconstituted microsomal ethanol-oxidizing system..Arch Biochem Biophys1978;191:798-803

[36] Ingelman-Sundberg M.Mechanisms of hydroxyl radical formation and ethanol oxidation by ethanol-inducible and other forms of rabbit liver microsomal cytochrome P-450..J Biol Chem1984;259:6447-58

[37] Lieber CS.The role of the hepatic microsomal ethanol-oxidizing system (MEOS) for ethanol metabolism in vivo..J Pharmacol Exp Ther1972;181:279-87

[38] Lieber CS,Matsuzaki S,Teschke R.Fleischer S.The microsomal ethanol-oxidizing system..Methods in Enzymology.1978;Academic Press: New York355-68

[39] Brooks PJ.DNA damage, DNA repair, and alcohol toxicity - a review..Alcohol Clin Exp Res1997;6:1073-82

[40] Baan R,Grosse Y,El Ghissassi F.Carcinogenicity of alcoholic beverages..Lancet Oncol2007;8:292-3

[41] Lachenmeier DW,Rehm J.Comparative risk assessment of carcinogens in alcoholic beverages using the margin of exposure approach..Int J Cancer2012;131:E995-1003

[42] Hart CL,Gruer L.The combined effect of smoking tobacco and drinking alcohol on cause-specific mortality: a 30 year cohort study..BMC Public Health2010;10:789 PMCID:PMC3022858

[43] Purohit V,Kwon OS.Roles of alcohol and tobacco exposure in the development of hepatocellular carcinoma..Life Sci2013;92:3-9 PMCID:PMC3822918

[44] Teschke R,Oldiges H.Effect of chronic alcohol consumption on tumor incidence due to dimethylnitrosamine administration..J Cancer Res Clin Oncol1983;106:58-64

[45] Gellert J,Haydn M,Frenzel H.Decreased hepatotoxicity of dimethylnitrosamine (DMN) following chronic alcohol consumption..Adv Exp Med Biol1980;132:237-43

[46] Teschke R.Effect of chronic alcohol pretreatment on the hepatotoxicity elicited by chlorpromazine, paracetamol, and dimethylnitrosamine..Biol Approach Alcohol Natl Inst Alcohol Abuse Alcohol Res Monogr1983;11:170-89

[47] Lieber CS.Alcohol and the liver: 1994 update..Gastroenterology1994;106:1085-105

[48] Lieber CS.Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis..Alcohol2004;34:9-19

[49] Neuman MG,Zakhari S,Seitz HK.Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage..Exp Mol Pathol2017;102:162-80

[50] Osna NA,Kharbanda KK.Alcoholic liver disease: pathogenesis and current management..Alcohol Res2017;38:147-61 PMCID:PMC5513682

[51] Basra S.Definition, epidemiology and magnitude of alcoholic hepatitis..World J Hepatol2011;3:108-13 PMCID:PMC3124876

[52] Day CP.Steatohepatitis: a tale of two “hits”?.Gastroenterology1998;114:842-4

[53] Teschke R.Alcoholic steatohepatitis (ASH) and acute alcoholic hepatitis (AH): Cascade of events, clinical features, and pharmacotherapy options..Exp Opin Pharmacother2018;19:779-93

[54] Fleming KM,Card TR.The rate of decompensation and clinical progression of disease in people with cirrhosis: a cohort study..Aliment Pharmacol Ther2010;32:1343-50

[55] Powell WJ Jr.Duration of survival in patients with Laennec’s cirrhosis. Influence of alcohol withdrawal, and possible effects of recent changes in general management of the disease..Am J Med1968;44:406-20

[56] Martini GA.Alcohol abstinence in alcoholic liver disease..Acta Med Scand1985;703:185-94

[57] O’Grady JG.Liver transplantation alcohol related liver disease: (Deliberately) stirring a hornet’s nest!.Gut2006;55:1529-31 PMCID:PMC1860102

[58] Matsushita H.Alcohol and the hepatocellular carcinoma..BMJ Open Gastroenterol2019;6:e000260

[59] Ganne-Carrié N.Hepatocellular carcinoma in the setting of alcohol-related liver disease..J Hepatol2019;70:284-93

[60] Schlageter M,D’Angelo S.Histopathology of hepatocellular carcinoma..World J Gastroenterol2014;20:15955-64 PMCID:PMC4239483

[61] Schlageter M,Matter M,Tornillo L.Clinicopathological features and metastatic pattern of hepatocellular carcinoma: an autopsy study of 398 patients..Pathobiology2016;83:301-7

[62] Mezale D, Strumfa I, Vanags A, Kalva A, Balosis D, et al. Diagnostic algorithm of hepatocellular carcinoma: classics and innovations in radiology and pathology. Intechopen 2018. Available from: https://www.intechopen.com/books/hepatocellular-carcinoma-advances-in-diagnosis-and-treatment/diagnostic-algorithm-of-hepatocellular-carcinoma-classics-and-innovations-in-radiology-and-pathology [last accessed on 7 Nov 2019]

[63] Marseglia L,D’Angelo G,Parisi E.Oxidative stress in obesity: a critical component in human diseases..Intl J Mol Sci2015;16:378-400 PMCID:PMC4307252

[64] Teschke R.Viewpoint: a contributory role of Shell ginger (Alpinia zerumbet) for human longevity of Okinawa in Japan?.Nutrients2018;10:166 PMCID:PMC5852742

[65] Mendez-Sanchez N,Ramirez-Perez OL,BarrancoFragoso B.New aspects of lipotoxicity in nonalcoholic steatohepatitis..Int J Mol Sci2018;19:E2034 PMCID:PMC6073816

[66] Davis GL,Meler JD,Walberg MW.Hepatocellular carcinoma: management of an increasingly common problem..Proc (Bayl Univ Med Cent)2008;21:266-80 PMCID:PMC2446418

[67] Nahon P,Trichet JC.Hepatic iron overload and risk of hepatocellular carcinoma in cirrhosis..Gastroenterol Clin Biol2010;34:1-7

[68] Anstee QM,Day CP.Genetics of alcoholic liver disease..Semin Liver Dis2015;35:361-74

[69] Donato F,Gelatti U,Boffetta P.Alcohol and hepatocellular carcinoma: the effect of life-time intake and hepatitis virus infections in men and women..Am J Epidemiol2002;155:323-31

[70] Péquinot G,Berta JL.Ascitic cirrhosis in relation to alcohol consumption..Int J Epidemiol1978;7:113-20

[71] Tuyns AJ.Greater risk of ascitic cirrhosis in females in relation to alcohol consumption..Int J Epidemiol1984;13:53-7

[72] Becker U,Sorensen TIA,Borch-Johnsen.Prediction of risk of liver disease by alcohol intake, sex, and age: a prospective population study..Hepatology1996;23:1025-9

[73] Caballeria J,Hernández-Muñoz R,Korsten MA.Gastric origin of the first-pass metabolism of ethanol in humans: effect of gastrectomy..Gastroenterology1989;97:1205-9

[74] Pavlov CS,Semenistaia M,Tsochatzis E.Ultrasonography for diagnosis of alcoholic cirrhosis in people with alcoholic liver disease..Cochrane Database Syst Rev2016;3:CD011602 PMCID:PMC6464787

[75] Bartolotta TV,Midiri M.Contrast-enhanced ultrasound of hepatocellular carcinoma: where do we stand?.Ultrasonography2019;38:200-14 PMCID:PMC6595127

[76] Forner A,Bruix J.Hepatocellular carcinoma..Lancet2018;391:1301-14

[77] Cohen JA.The SGOT/SGPT ratio an indicator of alcoholic liver disease..Dig Dis Sci1979;24:835-8

[78] Teschke R,Nishimura M.Hepatic gamma-glutamyltransferase activity in alcoholic fatty liver: comparison with other liver enzymes in man and rats..Gut1983;24:625-30 PMCID:PMC1420024

[79] Heckley GA,Asamoah BO.How the risk of liver cancer changes after alcohol cessation: a review and meta-analysis of the current literature..BMC Cancer2011;11:446 PMCID:PMC3229519

[80] Akinyemiju T,Ahmed M,Alemayohu MA.The burden of primary liver cancer and underlying etiologies from 1990 to 2015 at the global, regional, and national level: results from the global burden of disease study 2015..JAMA Oncol2017;3:1683-91 PMCID:PMC5824275