Development of hepatocellular carcinoma in viral B and viral C liver disease

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Slide 1 :

Development of hepatocellular carcinoma in viral B and viral C liver disease Monica Acalovschi, Rom J Gastroenterol 2003, 12, 123-130

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HCC epidemiology HCC = 85-90% of primary liver cancers Incidence 500,000 - 1,000 000 new cases / year 5th place among cancers in the world Mortality 3rd highest cause of cancer mortality Survival rates for untreated symptomatic HCC: 0% at 4 months ? 1% at 2 years

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Incidence and deaths:digestive cancers worldwide Men and women Incidence Deaths Colorectal 950 000 500 000 Stomach 875 000 650 000 Liver 560 000 550 000 Esophagus 400 000 330 000 Pancreas 200 000 200 000 Total (digestive cancers) 3 000 000 2 200 000 World Gastroenterology News 2003

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The geographic differences of HCC prevalence are mainly due to the predominant etiologic factors Hepatitis B and C viruses cause: > 75% of HCCs worldwide > 85% of HCCs in less developed countries HCC rates: ? in high risk populations (HBV infection decreases) ? in the low incidence areas (developed countries )

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HCC epidemiologic features Marked variation among geographic regions, racial and ethnic groups, and between men and women; Dynamic temporal trends; Presence of several well-documented environmental potentially preventive factors.

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A rising incidence of HCC has been evidenced in: Poland (Boron et al 1990) Australia (Brotodihardjo et al 1994) Romania (Acalovschi et al 1996) UK (Taylor Robinson et al 1997) Mexic (Cortes Espinosa 1997) West Scotland (De Vos Irvine et al 1998) France (Deuffic et al 1998) Sweden (Kaczynski et Oden 1999) USA (El-Serag 1999, 2001) Canada (elSaadany et al 2002) Japan (Okuda et al 1987, 1992)(? after 1997)

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The rising incidence of HCC in developed countries may reflect: an apparent increase; an age-effect, related to aging populations; a longer survival of cirrhotic patients due to a better treatment; a continuous influx of emigrants from areas with high HBV prevalence; a birth cohort effect; a rising incidence of HCV infection.

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Risk factors for HCC development in chronic liver diseases (1) Age HCC is an age-dependent cancer. It occurs at younger age in high-incidence areas. (2) Gender HCC prevalence is higher in men. Men/women = 3.7/1 in high-incidence areas 2.4/1 in low-incidence areas

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(3) Liver cirrhosis 70-90% of HCCs (> 90% in Western countries) = in cirrhotic livers HCC incidence: 2-4/100/year in viral B and 4-7/100/year in viral C liver cirrhosis. It is related to: male gender age (surrogate marker ?!) duration of disease disease activity (? viral replication, ? ALT etc) disease severity (Child C > B > A) Carcinogenesis: promotion via cycles of necrosis/regeneration ? ? susceptibility to environmental carcinogens

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(4) HCC risk (%) related to etiology

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Correlation of the geographic prevalence of HBV chronic carriers (350-400 millions) with HCC incidence

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Lines of evidence for a causal relationship between HBV infection and HCC (1) high incidence of HCC in HBV carriers: 1,158 / 100,000 in Taiwan (100x > non HBV carriers) 804 / 100,000 in Japan 657 / 100,000 in Canada, USA high prevalence of HBV in patients with HCC: in 70% in China in 24-27% in Japan in 41-56% in the USA HCC develops in 100% of woodchucks infected with the woodchuck hepatitis virus

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Lines of evidence derived from molecular biology techniques (2) HBsAg in the normal hepatocytes in HCC patients; HBsAg produced by cell lines from human HCC; HBV DNA integrated into tumor cell DNA in 95% of HCC pts ? carcinogenic effects (HBV = “complete carcinogen”) direct: mutations in HBV (in codons of HBV X gene, in S gene, in the precore region) indirect: instability of host DNA, perturbation of cellular oncogenes or tumor suppressor genes, increase of cell turnover rate, necrosis ~ regeneration cycles

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The carcinogenic risk in chronic HBV infection is increased by: HBV infection at birth ? lifetime risk of HCC: 50% in men, 20% in women male gender Asian or African race severity of liver disease simultaneous HCV or HDV infection exposure to aflatoxin (AFb1), alcohol, tobacco family history of HCC HBV genotype (C > B)(?)

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Lines of evidence for a causal relationship between HCV infection and HCC HCV incidence in developing countries is high HCV = major risk factor for HCC in developed countries HCC = major complication of viral C cirrhoses (19%); incidence = 4-7/100/year HCC occurs at an older age HCV prevalence in HCC patients: 5% in China 14 - 32% in the USA 54 - 70% in Japan HCV prevalence in HCC patients is increasing

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Estimation of the demographic history of HCV in the last century (“molecular clock”) Tanaka et al, PNAS 2002

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Mechanism of carcinogenesis in chronic HCV infection Indirect: via chronic necro-inflammation Carcinogenic risk enhanced by: older age at HCV acquisition infection through blood or blood-products co-infection with HBV or HIV male gender, obesity, alcohol (>50g/day), diabetes nuclear bombing exposure Direct: HCV RNA present in tumors in non-cirrhotic livers HCV core influences apoptosis, ? p53 activity..

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Molecular hepatocarcinogenesis Initiation exogenous agents (virus B or C) induce genetic lesions/DNA instability Promotion activation of protooncogenes inactivation of tumor suppressor genes DNA mismatch repair genes; telomerase activation; growth factors Setting: liver cell injury/necrosis + increased rate of hepatocyte regeneration and mitosis

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Primary prevention of HCC

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Incidence of HCC in children 6-14 and 0-5 yrs according to birth cohort Chang et al, N Engl J Med 1997

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Prevention of HCC Prevention of liver disease hygienic measures, prevention of exposure / vaccination against HBV Prevention of chronic hepatitis treatment of acute hepatitis C, abstinence from alcohol Prevention of liver cirrhosis antiviral treatment of chronic viral B and C hepatitis Prevention of HCC development in liver cirrhosis antiviral treatment (?), liver transplantation etc

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Probability of HCC in IFN-treated vs untreated pts with chronic hepatitis C Nishigushi et al, Lancet 2001

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Screening/surveillance for early detection of HCC

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Cumulated survival rates of HCC detected during follow up (1) and in unscreened pts (2) Bolondi et al, Gut 2001

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Cost-utility analysis Screening for HCC with CT and AFP is a cost-effective strategy in transplant-eligible patients with HCV cirrhosis, comparable with other commonly accepted interventions such as mammography and colonoscopy. Arguedas et al, Am J Gastroenterol 2003

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CONCLUSIONS AND FUTURE PROSPECTS HCC will continue to be a major challenge for the foreseeable future. Improved screening and diagnostic tools will probably improve survival of those affected with HCC. But unlike most malignancies, the greatest impact will likely be achieved with preventive strategies.

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