Secondary Logo

Journal Logo

Viruses and alcohol in the pathogenesis of primary hepatic carcinoma

Inoue, H1; Seitz, H K2

European Journal of Cancer Prevention: February 2001 - Volume 10 - Issue 1 - p 107-110
Symposium Proceedings
Free

1 Laboratory of Alcohol Research, Liver Disease and Nutrition; and 2 Department of Medicine, Salem Medical Center, Zepplinstrasse 11–33, D-69121 Heidelberg, Germany

Correspondence to: H K Seitz. Fax: (+49) 6221 483 494

*This paper was an invited presentation at the 18th Annual Symposium of European Cancer Prevention Organisation (ECP): Precancerous lesions of the digestive tract held in Maastricht, The Netherlands, 12–14 October, 2000

Back to Top | Article Outline

Introduction

Hepatocellular carcinoma (HCC) is one of the world's most common cancers, causing almost one million deaths per year. A major risk factor for the development of HCC is liver cirrhosis. Epidemiological studies show that over 80% of HCCs worldwide occur in a cirrhotic liver (Simonetti et al., 1997). In some areas of Asia and Africa the incidence of HCC is up to 120 per 100 000 (Muir et al., 1987). In addition to cirrhosis of the liver, major risk factors for HCC are chronic hepatitis B virus (HBV) infection and chronic hepatitis C virus infection, as well as chronic consumption of alcohol. HCC in these patients occurs primarily in the accompanying cirrhosis. However, both viruses may also initiate HCC without cirrhosis. Other risk factors include aflatoxin B1 exposure and a variety of metabolic liver diseases (Kountouras and Lygidakis, 2000). The purpose of this review is briefly to discuss the link between HCV and HBV infection and HCC, some pathogenic aspects and also the role of alcohol in the development of HCC.

Back to Top | Article Outline

Hepatitis B virus infection and HCC

Strong evidence exists that chronic infection with HBV is a risk factor for HCC. Chronic infection with HBV may cause approximately 80% of human HCC, and is frequently associated with cirrhosis of the liver. However, it has also been shown that HBV carriers have an increased risk about 100 times higher than that of controls for the development of HCC, which indicates a direct oncogenic role of HBV, independent of chronic hepatocellular injury (Johnson, 1997). A number of observations underline this aspect. HBsAg-positive cells have been found in tumours and HBV DNA integration has been detected in more than 75% of HCCs. Furthermore, in addition to free episomal genome length viral DNA forms, viral DNA integration can be detected in HCC (Johnson, 1997). Another factor is that HBV DNA integration occurs at early stages of HBV infection, is present during chronic hepatic infection and precedes the development of HCC. Subsequently, integrated viral DNA can directly induce chromosomal rearrangements (inversions, translocations, deletions) (Brechot, 1998). Several mechanisms for the oncogenic role of HBV have been proposed, including gene activation by integration of the viral cis -elements, induction of recombination by HBV subgenome, transactivation by viral proteins and continuous cell replication through immunological elimination of HBsAg-expressing liver cells (Schröder and Zentgraf, 1990;Schirmacher et al., 1993;Robinson, 1994; Caselman, 1995).

Integrated HBV DNA sequences frequently encode transactivating functions carried out by the hepatitis B virus x-protein (HBX) or carboxy-terminally truncated middle hepatitis B surface protein (MHBS t ) (Schlüter et al., 1994). HBX and MHBS t may transcriptionally activate a variety of viral promoters as well as promoters of cellular genes such as c-fos, c-myc and interferon β. Promoters are relevant for cell proliferation and transformation. More recently it has been shown that HBX may contribute to HCC development not only by transactivation but also by interaction with a cellular DNA repair system. This may lead to a decreased capacity to correct DNA adduct formation in the genome and may favour mutations (Dürr and Caselmann, 2000).

HBV and carcinogens may act synergistically in HCC development. This has been shown in mice, where HBV gene expression accelerates carcinogen-induced tumour development (Sell et al., 1991). For a more detailed account of the role of HBV in the pathogenesis of HCC the reader is referred to the recent review article by Kountouras and Lygidakis (2000).

Back to Top | Article Outline

Hepatitis C virus infection and HCC

Of patients with chronic hepatitis C virus infection, 0.4–2.5% develop HCC. HCC occurs more often in patients with cirrhosis of the liver. In a recent meta-analysis by Donato and co-workers (1998) it was shown that the mean risk for HCC was between 17- and 24-fold. These reviewed data only included prospective studies with an anti-HCV determination of the second generation and, in some, polymerase chain reaction (PCR). However, a few patients with HCC and HCV infection do not have cirrhosis (De Mitri et al., 1995). Prevalence of HCC was lower in carriers with persistently high values for transaminases or a histological diagnosis of chronic hepatitis compared with those with cirrhosis (Colombo, 1999). In a Japanese study, the 3-year cumulative risk of developing HCC was 12.5% for patients with cirrhosis and 3.8% for those with chronic hepatitis (Tsukuma et al., 1993). It seems that HCV subtype 1b is an additional risk factor for developing HCC (Bruno et al., 1997).

Pathogenesis of HCV-associated hepatocarcinogenesis is poorly understood and may possibly be related to the long-standing necro-inflammatory effect of HCV in the liver. However, the existence of patients with chronic HCV infection without cirrhosis who developed HCC, as well as experimental data suggest that HCV may be directly involved in hepatocarcinogenesis, with the products of the virus being involved in regulating liver cell proliferation. Evidence of a direct mechanism of HCV in tumour development is supported by the detection of minus strand HCV RNA in patients with HCC and with HCV infection (Niu et al., 1995). HCV may suppress apoptotic cell death, which may be one of the mechanisms involved. In addition HCV core protein expresses transcriptional activity of p53 in cell lines. Besides the fact that core protein expression inhibits cisplatin-mediated apoptosis in human cervical epithelial cells and apoptosis induced by c-myc overexpression in Chinese hamster ovary cells (Ray et al., 1996), the core protein may also have a transregulatory function in cellular and viral promoters and may, in cooperation with H-ras, transform primary rat embryo fibroblasts into a tumorigenic phenotype. For a more detailed discussion on the pathogenesis of HCV in HCC the reader is referred to the recent review article by Colombo (1999).

Back to Top | Article Outline

Hepatitis D virus infection

The role of HDV infection in liver oncogenesis remains unclear. Cirrhosis of the liver may be the underlying precancerous condition. HDV infections may possibly hasten development of HCC by accelerating the liver disease (Di Bisceglie and Hoofnagle, 1996).

Back to Top | Article Outline

Alcohol and HCC

Chronic alcohol consumption is a risk factor for HCC. The pathogenesis includes as a major prerequisite cirrhosis of the liver, concomitant infection with hepatitis B and hepatitis C virus, which is relatively common in the alcoholic, as well as some specific co-carcinogenic effects of alcohol itself. These effects include:

  • •The production of acetaldehyde, the first and most toxic metabolite of ethanol and its binding to DNA.
  • •The generation of free oxygen species via induced cytochrome P450 2E1.
  • •Increased activation environmental precarcinogens, especially of nitrosamines by cytochrome P450 2E1.
  • •Interaction between ethanol metabolism and the metabolism of retinol and retinoic acid resulting in decreased levels of retinoic acid in the liver and the production of toxic intermediates from retinol metabolism.
  • •The alteration of the nuclear DNA repair system.
  • •Concomitant dietary deficiency, which may play a role in carcinogenesis such as folate deficiency, which may lead to hypomethylation of DNA.

It has been shown that acetaldehyde binds to various cellular proteins and also to DNA (Seitz et al., 1998). Protein adducts, such as new antigens, initiate a cascade of immune responses. Acetaldehyde–DNA adducts may initiate carcinogenesis, especially since acetaldehyde by itself inhibits nuclear repair enzymes (Garro et al., 1986). Induction of cytochrome P450 2E1 by chronic alcohol consumption leads not only to increased acetaldehyde production but also to an increased generation of free oxygen radicals such as hydroxyethyl and hydroxymethyl radicals, which may be involved in carcinogenesis (Preedy and Seitz, 2001). In addition, cytochrome P450 2E1 induced by alcohol is the same cytochrome that also activates nitrosamines and various other procarcinogens to their ultimate carcinogenic form (Seitz and Osswald, 1992). More recent data focused on retinoic acid, an important factor in cell differentiation and cell regeneration. It has been shown that in the liver retinoic acid is extremely low after chronic alcohol consumption. This is associated with an increased expression of AP1 genes (c-fos and c-jun), leading to cellular hyperproliferation: early events in carcinogenesis. Supplementation of animals with retinoic acid results in normalization of AP1 gene expression and cellular regeneration (Wang et al., 1998;Seitz, 2000;Liu et al., 2001).

Back to Top | Article Outline

Chronic alcohol consumption, hepatitis B and C virus infection and HCC

HCC development in patients with hepatitis B infection is hastened by the concomitant consumption of alcohol. The mechanism is unclear, however it may act by increasing the severity of liver disease (Ohnishi et al., 1982).

More recently the relationship between alcohol intake and hepatitis C virus infection has been studied. High prevalence of HCV infection is noted in patients with alcoholic liver disease (Degos, 1999). Studies on the effect of alcohol intake below or over 40 g per day on the histological progression of liver lesions have confirmed a more rapid increase in fibrosis and a doubling in the incidence of cirrhosis in patients admitting to alcohol consumption of more than 40 g per day (Wiley et al., 1998). Patients with hepatitis C virus infection have a doubled risk of developing HCC when they consume alcohol heavily. It has also been shown that even small amounts of alcohol lead to an increased level of serum HCV RNA in patients with HCV infection (Cromie et al., 1996). Alcohol also increases the dermatological effects of HCV infection such as porphyria cutanea tarda. As a conclusion, patients with hepatitis B and hepatitis C virus infection should abstain from alcohol completely.

Back to Top | Article Outline

Uncited references

Caselmann, 1995;Donato et al., 1998

Back to Top | Article Outline

References

1. Brechot C ( 1998 ). Molecular mechanisms of hepatitis B and C viruses related to liver carcinogenesis . Hepato-Gastroenterology 45 : 1189 – 1196 .
2. Bruno S , Silini E , Crosignani A et al. ( 1997 ). Hepatitis C virus genotypes and risk of hepatocellular carcinoma in cirrhosis: a prospective study . Hepatology 25 : 754 – 758 .
3. Caselmann WH ( 1995 ). Transactivation of cellular gene expression by hepatitis B viral proteins: a possible molecular mechanism of hepatocarcinogenesis . J Hepatol 22 ( Suppl 1 ): 34 – 37 .
4. Colombo M ( 1999 ). Natural history and pathogenesis of hepatitis C virus related hepatocellular carcinoma . J Hepatol 31 ( Suppl 1 ): 25 – 30 .
5. Cromie SL , Jenkins PJ , Bowden DS , Dudley FJ ( 1996 ). Chronic hepatitis C: effect of alcohol on hepatic activity and viral titre . J Hepatol 25 : 821 – 826 .
6. De Mitri MS , Poussin K , Baccarini P et al. ( 1995 ). HCV-associated liver cancer without cirrhosis . Lancet 345 : 413 – 415 .
7. Degos F ( 1999 ). Hepatitis C and alcohol . J Hepatol 31 ( Suppl 1 ): 113 – 118 .
8. Di Bisceglie AD , Hoofnagle JH ( 1996 ). Chronic viral hepatitis . In Hepatology (eds Zakim D , Boyer TD ); WB Saunders , Philadelphia , pp. 1299 – 1329 .
9. Donato F , Boffetta P , Puoti M ( 1998 ). A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma . Int J Cancer 75 : 347 – 354 .
10. Dürr R , Caselmann WH ( 2000 ). Carcinogenesis of primary liver malignancies . Langenbed's Arch Surg 385 : 154 – 161 .
11. Garro AJ , Espina N , Farinati F et al. ( 1986 ). The effect of chronic ethanol consumption on carcinogen metabolism and on O6-methylguanine transferase-mediated repair of alkylated DNA . Alcohol Clin Exp Res 10 : 73 – 77 .
12. Johnson RC ( 1997 ). Hepatocellular carcinoma . Hepato-Gastroenterology 44 : 307 – 312 .
13. Kountouras J , Lygidakis NJ ( 2000 ). New epidemiological data on liver oncogenesis . Hepato-Gastroenterology 47 ( 33 ): 855 – 861 .
14. Liu C, Russel RM, Seitz HK, Wang XD (2001). Ethanol enhances retinoic acid metabolism into polar metabolites in rat liver via induction of cytochrome P450 2E1. Gastroenterology (in press).
15. Muir C, Waterhouse J, Mack T, Dowell J, Whelan S (1987). Cancer Incidence in Five Continents. Vol V. World Health Organization, IARC Scientific Publication No. 88. IARC, Lyon.
16. Niu J , Kumar U , Monjardino J et al. ( 1995 ). Hepatitis C virus replication in hepatocellular carcinoma . J Clin Pathol 48 : 880 – 882 .
17. Ohnishi K , Iida S , Iwama S et al. ( 1982 ). The effect of chronic habitual alcohol intake on the development of liver cirrhosis and hepatocellular carcinoma: relation to hepatitis B surface antigen carriers . Cancer 49 : 672 – 677 .
18. Preedy VR, Seitz HK (2001). Oxidative stress, cell damage and its possible prevention by alpha tocopherol: cardiovascular and other cells. In Alcohol and Heart Disease (eds Watson RR, Myers A); Harwood Academic Publication, Overseas Publishing Associates, OPA (in press).
19. Ray RB , Lagging LM , Meyer K , Ray R ( 1996 ). Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype . J Virol 70 : 4438 – 4443 .
20. Robinson WS ( 1994 ). Molecular events in the pathogenesis of hepadnavirus-associated hepatocellular carcinoma . Annu Rev Med 45 : 297 – 323 .
21. Schirmacher P , Rogler CE , Denes HP ( 1993 ). Current pathogenic and molecular concept in viral liver carcinogenesis . Virchows Arch B Cell Pathol Incl Mol Pathol 63 : 71 – 89 .
22. Schlüter V , Meyer M , Hofschneider PH , Kochy R , Caselmann WH ( 1994 ). Integrated hepatitis B virus X and 3′ truncated preS/S sequences derived from human hepatomas encode functionally active transactivators . Oncogene 9 : 3335 – 3344 .
23. Schröder CH , Zentgraf H ( 1990 ). Hepatitis B virus related hepatocellular carcinoma: chromacry of infection – the opening to different pathways of malignant transformation? . Biochim Biophys Acta 1032 : 137 – 156 .
24. Seitz HK ( 2000 ). Alcohol and retinoid metabolism . Gut 47 : 748 – 750 .
25. Seitz HK , Osswald B ( 1992 ). Effects of ethanol on procarcinogen . In Alcohol and Cancer (ed Galanter M ); CRC Press , Boca Raton , pp. 67 – 95 .
26. Seitz HK , Pöschl G , Simanowski UA ( 1998 ). Alcohol and cancer . In Recent Developments in Alcoholism, Vol 14: The Consequences of Alcoholism (ed Galanter M ); Plenum Press , New York , pp. 67 – 95 .
27. Sell S , Hunt JM , Dunsford HA , Chisari FV ( 1991 ). Synergy between hepatitis B virus expression and chemical hepatocarcinogens in transgenic mice . Cancer Res 51 : 1278 – 1285 .
28. Simonetti RG , Liberati A , Angiolini C , Pagliaro L ( 1997 ). Treatment of hepatocellular carcinoma: a systematic review of randomized controlled trials . Ann Oncol 8 : 117 – 136 .
29. Tsukuma H , Hiyama T , Tanaka S et al. ( 1993 ). Risk factors for hepatocellular carcinoma among patients with chronic liver disease . N Engl J Med 328 : 1797 – 1801 .
30. Wang XD , Liu C , Chung J et al. ( 1998 ). Chronic alcohol intake reduces retinoic acid concentration and enhances AP-1 (c-Jun and c-Fos) expression in rat liver . Hepatology 25 : 744 – 750 .
31. Wiley TE , McCarthy M , Breidi L , McCarthy M , Layden TJ ( 1998 ). Impact of alcohol on the histological and clinical progression of hepatitis C infection . Hepatology 28 : 805 – 809 .
Keywords:

Alcohol; carcinogenesis; cytochrome P450 2E1; hepatitis B virus; hepatitis C virus; hepatocellular carcinoma; liver disease.

© 2001 Lippincott Williams & Wilkins, Inc.